1 00:00:17,010 --> 00:00:18,780 PROFESSOR: OK so on Monday we talked 2 00:00:18,780 --> 00:00:22,950 about how cell division is regulated at this single cell 3 00:00:22,950 --> 00:00:24,180 level. 4 00:00:24,180 --> 00:00:28,470 On Wednesday we talked about how regeneration 5 00:00:28,470 --> 00:00:32,070 is mediated at the level of an entire tissue. 6 00:00:32,070 --> 00:00:34,470 And today we're going to talk about how all of that 7 00:00:34,470 --> 00:00:36,210 can go wrong, OK? 8 00:00:36,210 --> 00:00:39,120 And when all of this goes wrong, it 9 00:00:39,120 --> 00:00:43,740 results in a disease, actually many different diseases, 10 00:00:43,740 --> 00:00:48,070 but are commonly known as cancer. 11 00:00:48,070 --> 00:00:52,110 And as illustrated in this cartoon, what you see 12 00:00:52,110 --> 00:00:57,090 is that cancer can often be defined 13 00:00:57,090 --> 00:01:02,220 as having distinct steps in its progressive, essentially, 14 00:01:02,220 --> 00:01:08,340 deregulation of normal cell and tissue behavior. 15 00:01:08,340 --> 00:01:11,760 So when we're thinking about cancer, 16 00:01:11,760 --> 00:01:17,460 we're thinking about a stepwise degeneration. 17 00:01:21,610 --> 00:01:27,130 And cancer is a disease that affects an individual's 18 00:01:27,130 --> 00:01:31,330 own cells, but those cells get progressively and progressively 19 00:01:31,330 --> 00:01:35,890 dysregulate d in their behavior and the coordination 20 00:01:35,890 --> 00:01:38,810 of their behavior with the rest of the tissue. 21 00:01:38,810 --> 00:01:45,385 So it's a stepwise degeneration of normal cell behavior. 22 00:01:48,340 --> 00:01:56,500 And it results from mutations that are occurring in the cell. 23 00:01:56,500 --> 00:02:01,420 And we'll talk about what types of mutations right now. 24 00:02:01,420 --> 00:02:04,420 And then I'll take you through some examples 25 00:02:04,420 --> 00:02:06,730 of different signaling pathways and we'll 26 00:02:06,730 --> 00:02:12,220 try to classify what different types of genes 27 00:02:12,220 --> 00:02:15,550 should be labeled as. 28 00:02:15,550 --> 00:02:19,377 So first, I want to talk about classes of genes 29 00:02:19,377 --> 00:02:20,710 and their involvement in cancer. 30 00:02:25,690 --> 00:02:28,570 And the first example that I'll take you through 31 00:02:28,570 --> 00:02:30,190 is known as an oncogene. 32 00:02:35,770 --> 00:02:38,680 And it's referred to as an oncogene 33 00:02:38,680 --> 00:02:41,530 after the mutation has already happened. 34 00:02:41,530 --> 00:02:45,970 And so an oncogenic mutation is a mutation 35 00:02:45,970 --> 00:02:50,720 that's going to promote growth and survival of a cell. 36 00:02:50,720 --> 00:02:52,600 So this promotes growth. 37 00:02:57,970 --> 00:03:01,270 Before the gene is mutated, it's referred 38 00:03:01,270 --> 00:03:03,730 to as a proto-oncogene. 39 00:03:03,730 --> 00:03:13,880 So before mutated, the gene is labeled a proto-oncogene. 40 00:03:20,590 --> 00:03:23,500 And the normal function of these proto-oncogenes 41 00:03:23,500 --> 00:03:26,410 is also to promote growth and survival, 42 00:03:26,410 --> 00:03:30,010 but they do so in a regulated manner. 43 00:03:30,010 --> 00:03:33,070 So a gene becomes an oncogene when 44 00:03:33,070 --> 00:03:35,230 there's a mutation that causes it 45 00:03:35,230 --> 00:03:39,910 to be unregulated by the environment of the cell 46 00:03:39,910 --> 00:03:42,250 or even the surroundings of the cell. 47 00:03:42,250 --> 00:03:48,460 And so you can think of this as a constitutive activation. 48 00:03:48,460 --> 00:03:52,060 Often oncogenes are constitutively active forms 49 00:03:52,060 --> 00:03:52,915 of normal genes. 50 00:03:57,940 --> 00:04:00,370 And one way to think about this is 51 00:04:00,370 --> 00:04:05,500 you have a gene whose normal function is to promote growth 52 00:04:05,500 --> 00:04:09,010 and it's kind of stuck in the state of the gene that 53 00:04:09,010 --> 00:04:12,690 always promotes growth, which is not normally how it works. 54 00:04:12,690 --> 00:04:17,019 Normally there are signals that tell a cell to grow, 55 00:04:17,019 --> 00:04:19,810 and those signals come and go, and that's 56 00:04:19,810 --> 00:04:23,290 how the body regulates when cells divide. 57 00:04:23,290 --> 00:04:27,370 But you can have a situation where it's essentially 58 00:04:27,370 --> 00:04:31,540 the equivalent of what you might consider a stuck accelerator, 59 00:04:31,540 --> 00:04:33,750 if you're thinking about an automobile. 60 00:04:33,750 --> 00:04:36,280 So if you have a stuck accelerator, 61 00:04:36,280 --> 00:04:39,340 and you can only speed up, and you can't slow down, 62 00:04:39,340 --> 00:04:42,640 this is analogous to an oncogenic mutation. 63 00:04:47,080 --> 00:04:49,960 Now a different class of gene, actually 64 00:04:49,960 --> 00:04:52,660 kind of the opposite of an oncogene, 65 00:04:52,660 --> 00:04:54,270 is called a tumor suppressor. 66 00:05:01,850 --> 00:05:06,050 And tumor suppressors are genes whose normal function 67 00:05:06,050 --> 00:05:11,270 is to inhibit growth or even promote death. 68 00:05:11,270 --> 00:05:21,120 So tumor suppressors inhibit growth or promote death. 69 00:05:21,120 --> 00:05:23,940 You could see how these two different things would 70 00:05:23,940 --> 00:05:27,390 have the same effect in that it's not 71 00:05:27,390 --> 00:05:30,000 allowing one cell to become a lot of cells 72 00:05:30,000 --> 00:05:32,820 because the tumor suppressor will either prevent it 73 00:05:32,820 --> 00:05:37,120 from dividing or will cause the cells to die. 74 00:05:37,120 --> 00:05:40,920 And so the cancer phenotype is associated 75 00:05:40,920 --> 00:05:44,880 with a loss of function of the tumor suppressor. 76 00:05:44,880 --> 00:05:49,800 So these result from loss of function mutations in the tumor 77 00:05:49,800 --> 00:05:52,680 suppressors. 78 00:05:52,680 --> 00:05:56,490 So if you remove the thing that's inhibiting growth, 79 00:05:56,490 --> 00:05:59,700 then that allows the cells to divide 80 00:05:59,700 --> 00:06:01,410 in a more unregulated way. 81 00:06:04,230 --> 00:06:08,700 And so sticking with the analogy of an automobile, 82 00:06:08,700 --> 00:06:12,480 you could think of the tumor suppressor mutation 83 00:06:12,480 --> 00:06:15,060 as a cell having defective brakes. 84 00:06:15,060 --> 00:06:18,060 So you can think of this as defective brakes. 85 00:06:29,810 --> 00:06:35,270 So it's the loss of function of these that lead to cancer. 86 00:06:35,270 --> 00:06:38,120 Now I want to tell you about one last class of genes 87 00:06:38,120 --> 00:06:40,550 that are implicated in cancer. 88 00:06:40,550 --> 00:06:43,970 And these are what, in the diagram up there, 89 00:06:43,970 --> 00:06:46,010 are referred to as caretaker genes. 90 00:06:50,510 --> 00:06:52,970 And what that refers to is the fact 91 00:06:52,970 --> 00:06:56,540 that these genes are involved in maintaining 92 00:06:56,540 --> 00:06:59,930 the genomic integrity of a cell. 93 00:06:59,930 --> 00:07:03,470 And they can do that by mediating DNA 94 00:07:03,470 --> 00:07:06,660 repair when it needs to happen. 95 00:07:06,660 --> 00:07:16,320 So these are involved in the repair of DNA. 96 00:07:16,320 --> 00:07:19,790 Or actually, I know what I'll say. 97 00:07:19,790 --> 00:07:22,370 We'll say genome. 98 00:07:22,370 --> 00:07:26,510 It's involved in genome repair. 99 00:07:26,510 --> 00:07:31,170 But not only repair, but also genome stability. 100 00:07:31,170 --> 00:07:35,600 So making sure that chromosomes are equally 101 00:07:35,600 --> 00:07:38,390 segregated to daughter cells so that you don't end up 102 00:07:38,390 --> 00:07:40,340 with cells with extra chromosomes 103 00:07:40,340 --> 00:07:42,590 or lacking entire chromosomes, which 104 00:07:42,590 --> 00:07:44,720 is known as being aneuploid. 105 00:07:44,720 --> 00:07:48,500 So genome repair and also integrity. 106 00:07:54,500 --> 00:07:59,570 And again, because these promote genome integrity, 107 00:07:59,570 --> 00:08:03,140 it's a loss of the function of these genes 108 00:08:03,140 --> 00:08:06,170 that is what promotes cancer. 109 00:08:06,170 --> 00:08:12,980 So a loss of function mutations in caretaker genes 110 00:08:12,980 --> 00:08:16,820 are what can drive a cancer phenotype. 111 00:08:16,820 --> 00:08:20,360 And that's because if you lose a caretaker gene that's 112 00:08:20,360 --> 00:08:27,560 involved in DNA repair, actually one example of a caretaker gene 113 00:08:27,560 --> 00:08:33,000 is the BRCA1 gene, which is involved in breast cancer. 114 00:08:33,000 --> 00:08:36,919 And so if you lack this BRCA1 gene, 115 00:08:36,919 --> 00:08:40,190 it makes it so that the cells are not 116 00:08:40,190 --> 00:08:42,380 as good at repairing their DNA. 117 00:08:42,380 --> 00:08:46,580 And then the cell can accumulate additional mutations, 118 00:08:46,580 --> 00:08:49,730 and the cell might get an oncogenic mutation 119 00:08:49,730 --> 00:08:52,160 or it might lose tumor suppressors. 120 00:08:52,160 --> 00:08:54,680 And that's what drives that cancer phenotype. 121 00:08:58,130 --> 00:09:01,430 Now I just want to point out something that just happened 122 00:09:01,430 --> 00:09:05,420 this week, which is that one of our very own colleagues 123 00:09:05,420 --> 00:09:10,280 here at MIT, Angelika Amon, whose lab has 124 00:09:10,280 --> 00:09:15,320 done a lot of research that has provided fundamental insights 125 00:09:15,320 --> 00:09:19,700 into how a lack of genome integrity 126 00:09:19,700 --> 00:09:23,990 influences both normal and cancer cells. 127 00:09:23,990 --> 00:09:28,340 She just won what's known as the breakthrough prize. 128 00:09:28,340 --> 00:09:33,740 And so this is a prize that was initiated by Chan Zuckerberg 129 00:09:33,740 --> 00:09:36,470 initiative, so it's out of Silicon Valley. 130 00:09:36,470 --> 00:09:40,430 And the point of the prize is to basically celebrate science, 131 00:09:40,430 --> 00:09:43,490 like we would movies at the Oscars. 132 00:09:43,490 --> 00:09:47,360 And so this is Angelika here receiving this breakthrough 133 00:09:47,360 --> 00:09:50,630 award, and this just happened this past weekend. 134 00:09:50,630 --> 00:09:53,060 And this is for her fundamental work 135 00:09:53,060 --> 00:09:57,560 on how aneuploidy influences the biology not only 136 00:09:57,560 --> 00:10:00,950 of normal cells, but also cancer cells because it 137 00:10:00,950 --> 00:10:04,100 plays an important role in the biology of cancer. 138 00:10:06,860 --> 00:10:08,720 All right, so now that we've defined 139 00:10:08,720 --> 00:10:11,450 some of these key genes, I want to talk 140 00:10:11,450 --> 00:10:17,510 about one example of a pathway that influences cell division. 141 00:10:17,510 --> 00:10:20,270 And we'll go through all of the genes in this pathway 142 00:10:20,270 --> 00:10:22,010 and decide whether or not they should 143 00:10:22,010 --> 00:10:28,430 be considered oncogenes, tumor suppressors, or caretakers. 144 00:10:28,430 --> 00:10:31,490 And the pathway we're going to look at 145 00:10:31,490 --> 00:10:33,950 involves the G1 to S transition. 146 00:10:37,890 --> 00:10:40,160 And you'll recall that this G1 to S 147 00:10:40,160 --> 00:10:45,860 transition in the cell cycle is referred to as START 148 00:10:45,860 --> 00:10:49,160 and is the point at which an individual cell commits 149 00:10:49,160 --> 00:10:53,030 to going through the entire cell cycle. 150 00:10:53,030 --> 00:10:56,210 So this G1 S transition, or START, 151 00:10:56,210 --> 00:11:01,970 what kicks off the whole process is the expression of a cyclin. 152 00:11:01,970 --> 00:11:04,550 And that is specifically the G1 cyclin. 153 00:11:08,600 --> 00:11:15,290 And this G1 cyclin is regulated by many different things. 154 00:11:15,290 --> 00:11:17,900 And we've talked about a lot of them. 155 00:11:17,900 --> 00:11:22,170 First of all, there are growth signals. 156 00:11:22,170 --> 00:11:26,330 These are secreted proteins that allow cells 157 00:11:26,330 --> 00:11:28,310 to communicate with each other. 158 00:11:28,310 --> 00:11:32,330 And many growth signals promote growth and cell division 159 00:11:32,330 --> 00:11:35,240 by up regulating this G1 cyclin. 160 00:11:35,240 --> 00:11:38,030 So you're actually regulating the gene expression 161 00:11:38,030 --> 00:11:42,380 of this particular cyclin gene. 162 00:11:42,380 --> 00:11:44,930 We also talked about Wnt. 163 00:11:44,930 --> 00:11:48,040 And Wnt is another type of signaling system. 164 00:11:48,040 --> 00:11:52,870 And one of its targets is also the G1 cyclin. 165 00:11:52,870 --> 00:11:55,660 So both of these signals promote growth. 166 00:11:55,660 --> 00:11:58,390 There are also other types of signals, 167 00:11:58,390 --> 00:12:03,200 like cytokines, which also promote G1 cyclin expression. 168 00:12:03,200 --> 00:12:06,610 So this is a really pivotal control point 169 00:12:06,610 --> 00:12:08,650 for the cell to decide whether or not 170 00:12:08,650 --> 00:12:11,470 to enter into the cell cycle. 171 00:12:11,470 --> 00:12:13,660 I'll point out that there are also 172 00:12:13,660 --> 00:12:16,840 other types of signals that inhibit growth, 173 00:12:16,840 --> 00:12:19,990 and I'll call those growth inhibitors. 174 00:12:19,990 --> 00:12:23,900 And so these growth inhibitors inhibit G1 cyclin expression. 175 00:12:23,900 --> 00:12:26,560 So if you have a cell in your body, 176 00:12:26,560 --> 00:12:30,180 and it's trying to decide whether or not to divide, 177 00:12:30,180 --> 00:12:34,250 it's basically reading out how many growth positive signals 178 00:12:34,250 --> 00:12:37,300 it's seeing versus growth negative signals, 179 00:12:37,300 --> 00:12:40,600 and it's able to integrate that information based 180 00:12:40,600 --> 00:12:43,600 on how much G1 cyclin it produces, 181 00:12:43,600 --> 00:12:45,190 and that determines whether or not 182 00:12:45,190 --> 00:12:48,640 it goes into the cell cycle. 183 00:12:48,640 --> 00:12:51,910 So G1 cyclin. 184 00:12:51,910 --> 00:12:55,000 And G1 cyclin functions with cyclin-dependent kinase. 185 00:12:55,000 --> 00:12:58,150 So this depends on cyclin-dependent kinase. 186 00:12:58,150 --> 00:13:01,990 This eventually leads to the expression of the G1 187 00:13:01,990 --> 00:13:04,510 to S cyclin. 188 00:13:04,510 --> 00:13:07,420 And it's the G1 to S cyclin which 189 00:13:07,420 --> 00:13:12,550 is responsible for activating the transition from G1 to S, 190 00:13:12,550 --> 00:13:16,030 which is known as START in yeast and the restriction 191 00:13:16,030 --> 00:13:18,610 point in mammalian cells. 192 00:13:18,610 --> 00:13:22,780 But it all starts really with this G1 cyclin. 193 00:13:22,780 --> 00:13:27,070 So I want to talk about this step in the cell cycle. 194 00:13:27,070 --> 00:13:30,400 And I'll show you the nitty gritty of the mechanisms that 195 00:13:30,400 --> 00:13:31,540 are involved. 196 00:13:31,540 --> 00:13:35,650 And we'll talk about what types of genes all of these genes 197 00:13:35,650 --> 00:13:36,310 are. 198 00:13:36,310 --> 00:13:39,130 And it's going to involve a very important gene 199 00:13:39,130 --> 00:13:42,910 that I'm going to tell you a lot more about in just 200 00:13:42,910 --> 00:13:44,870 a few minutes. 201 00:13:44,870 --> 00:13:49,210 All right, so the critical determinant of START 202 00:13:49,210 --> 00:13:51,100 is this G1 S cyclin. 203 00:13:51,100 --> 00:13:53,890 So I'm drawing a piece of DNA here. 204 00:13:53,890 --> 00:13:56,680 Here's the G1 S cyclin gene. 205 00:13:56,680 --> 00:13:57,760 So this is DNA. 206 00:13:57,760 --> 00:13:59,830 I just drew a piece of DNA. 207 00:13:59,830 --> 00:14:01,370 Part of the genome. 208 00:14:01,370 --> 00:14:06,550 This is the G1 S cyclin gene. 209 00:14:06,550 --> 00:14:09,940 And this gene is activated, its transcription 210 00:14:09,940 --> 00:14:15,290 is activated, by a transcription factor known as E2F. 211 00:14:15,290 --> 00:14:17,320 So we'll keep track of what these are. 212 00:14:17,320 --> 00:14:20,425 E2F is a transcription factor. 213 00:14:28,390 --> 00:14:30,700 So E2F is a transcription factor that 214 00:14:30,700 --> 00:14:35,920 will activate the expression of this G1 S cyclin. 215 00:14:35,920 --> 00:14:43,310 But in early G1, there's a protein that binds to E2F. 216 00:14:43,310 --> 00:14:45,820 And this protein is called Rb. 217 00:14:45,820 --> 00:14:48,950 I'll tell you what Rb stands for in just a minute. 218 00:14:48,950 --> 00:14:52,840 But what Rb does is it binds to E2F 219 00:14:52,840 --> 00:14:56,650 and it inhibits its transcriptional activity. 220 00:14:56,650 --> 00:15:01,780 So in early G1, E2F is inhibited and the expression 221 00:15:01,780 --> 00:15:04,840 of this G1 cyclin is off. 222 00:15:04,840 --> 00:15:08,230 So this is off or repressed. 223 00:15:11,750 --> 00:15:17,960 So before the cell passes START, this expression is off. 224 00:15:17,960 --> 00:15:20,800 So this is early G1 before START. 225 00:15:26,060 --> 00:15:32,720 Now what happens is this state is changed by the G1 cyclin. 226 00:15:32,720 --> 00:15:36,680 So if there's adequate levels of G1 cyclin, and this 227 00:15:36,680 --> 00:15:39,800 is in complex with cyclin-dependent kinase. 228 00:15:39,800 --> 00:15:42,560 Because cyclins, their functions are always 229 00:15:42,560 --> 00:15:45,140 mediated through cyclin-dependent kinase. 230 00:15:45,140 --> 00:15:48,170 So the cyclins are never, as far as I know, functioning 231 00:15:48,170 --> 00:15:49,790 on there by themselves. 232 00:15:49,790 --> 00:15:52,160 They're always functioning through one 233 00:15:52,160 --> 00:15:55,400 of the cyclin-dependent kinases. 234 00:15:55,400 --> 00:16:00,620 So G1 cyclin CDK phosphorylates Rb. 235 00:16:00,620 --> 00:16:05,840 And so you then get an Rb that has a bunch of phosphates 236 00:16:05,840 --> 00:16:06,560 attached to it. 237 00:16:10,040 --> 00:16:16,250 And this inhibits Rb's function such that it can't bind to E2F. 238 00:16:16,250 --> 00:16:21,530 So when G1 cyclin CDK phosphorylates Rb, 239 00:16:21,530 --> 00:16:27,400 that causes Rb to go away from the promoter of the G1 S 240 00:16:27,400 --> 00:16:28,400 cyclin. 241 00:16:28,400 --> 00:16:32,120 And now you have this transcription factor, E2F, 242 00:16:32,120 --> 00:16:35,940 free to transcribe the G1 S cyclin gene. 243 00:16:35,940 --> 00:16:38,180 So this now gets turned on. 244 00:16:40,910 --> 00:16:45,180 And it's this activation of G1 S gene expression 245 00:16:45,180 --> 00:16:49,010 which is the signal to undergo. 246 00:16:49,010 --> 00:16:57,470 You get G1 S cyclin CDK because you express this gene. 247 00:16:57,470 --> 00:17:00,970 And that activates the transition into S phase. 248 00:17:09,550 --> 00:17:11,990 All right, now take a look at everything 249 00:17:11,990 --> 00:17:14,270 I just drew on the board. 250 00:17:14,270 --> 00:17:17,450 Who can tell me where the tumor suppressors 251 00:17:17,450 --> 00:17:18,410 are in this pathway? 252 00:17:22,750 --> 00:17:24,534 Miles. 253 00:17:24,534 --> 00:17:26,740 MILES: Rb. 254 00:17:26,740 --> 00:17:28,240 PROFESSOR: Rb is a tumor suppressor. 255 00:17:28,240 --> 00:17:29,440 That's exactly right. 256 00:17:29,440 --> 00:17:32,200 Let me get some colored chalk here. 257 00:17:34,870 --> 00:17:42,070 All right, I'm going to circle tumor suppressors in pink. 258 00:17:42,070 --> 00:17:45,290 Are there any other tumor suppressors? 259 00:17:45,290 --> 00:17:48,660 So Rb is a tumor suppressor. 260 00:17:48,660 --> 00:17:49,270 Yeah, Amanda. 261 00:17:52,870 --> 00:17:54,570 Did you have one, Amanda? 262 00:17:54,570 --> 00:17:55,150 Georgia. 263 00:17:55,150 --> 00:17:56,850 Georgia, sorry. 264 00:17:56,850 --> 00:17:58,810 GEORGIA: The growth inhibitors. 265 00:17:58,810 --> 00:18:01,480 PROFESSOR: The growth inhibitors are also tumor suppressors, 266 00:18:01,480 --> 00:18:01,980 exactly. 267 00:18:08,170 --> 00:18:11,230 OK, how about oncogenes? 268 00:18:11,230 --> 00:18:15,340 What would be considered a proto-oncogene in this system? 269 00:18:15,340 --> 00:18:16,215 Jeremy? 270 00:18:16,215 --> 00:18:17,537 JEREMY: CDK. 271 00:18:17,537 --> 00:18:20,390 PROFESSOR: CDK would be one, yup. 272 00:18:20,390 --> 00:18:21,490 So oncogenes. 273 00:18:26,260 --> 00:18:29,200 CDK can be considered a proto-oncogene. 274 00:18:29,200 --> 00:18:30,010 Anything else? 275 00:18:36,500 --> 00:18:40,220 Well, what defines an oncogene or a proto-oncogene? 276 00:18:40,220 --> 00:18:42,310 What's its normal function in the cell? 277 00:18:46,030 --> 00:18:48,020 Carmen? 278 00:18:48,020 --> 00:18:51,460 CARMEN: Its function is to move the cell along the cell cycle. 279 00:18:51,460 --> 00:18:53,040 PROFESSOR: Yes. 280 00:18:53,040 --> 00:18:54,570 So it promotes growth. 281 00:18:54,570 --> 00:18:58,470 And moving a cell along the cell cycle will promote growth. 282 00:18:58,470 --> 00:19:00,960 So yes, exactly. 283 00:19:00,960 --> 00:19:04,605 So anything here promoting growth besides CDK? 284 00:19:04,605 --> 00:19:06,000 CARMEN: E2F. 285 00:19:06,000 --> 00:19:10,230 PROFESSOR: E2F would be a proto-oncogene, sure. 286 00:19:10,230 --> 00:19:11,805 Jeremy, did you have an idea? 287 00:19:11,805 --> 00:19:13,020 JEREMY: G1 cyclin. 288 00:19:13,020 --> 00:19:14,400 PROFESSOR: G1 cyclin. 289 00:19:14,400 --> 00:19:17,100 Basically everything else here would be considered 290 00:19:17,100 --> 00:19:19,020 a proto-oncogene, right? 291 00:19:19,020 --> 00:19:20,400 Wnts are proto-oncogenes. 292 00:19:20,400 --> 00:19:22,140 They're promoting growth by promoting 293 00:19:22,140 --> 00:19:25,470 the expression of G1 cyclin. 294 00:19:25,470 --> 00:19:28,020 The growth signaling pathway, all of those genes 295 00:19:28,020 --> 00:19:30,390 would be considered proto-oncogenes. 296 00:19:30,390 --> 00:19:33,510 And so anything that is promoting growth 297 00:19:33,510 --> 00:19:35,160 will be a proto-oncogene here. 298 00:19:37,900 --> 00:19:38,400 Great. 299 00:19:41,520 --> 00:19:45,630 All right, so now we're going to move on and talk about this Rb 300 00:19:45,630 --> 00:19:49,380 gene, which I just showed you mechanistically what it does. 301 00:19:49,380 --> 00:19:52,930 But what Rb stands for is retinoblastoma. 302 00:19:58,950 --> 00:20:02,250 So Rb stands for retinoblastoma. 303 00:20:02,250 --> 00:20:05,310 And this Rb gene, as you suggested, 304 00:20:05,310 --> 00:20:06,960 is a tumor suppressor. 305 00:20:06,960 --> 00:20:11,820 It was actually the first tumor suppressor that was cloned. 306 00:20:11,820 --> 00:20:16,510 And so retinoblastoma, as the name implies, 307 00:20:16,510 --> 00:20:19,500 is involved in a human disease. 308 00:20:19,500 --> 00:20:28,830 And it's involved in a rare childhood eye tumor. 309 00:20:34,870 --> 00:20:38,290 So I'm going to show you one last weird eye picture. 310 00:20:38,290 --> 00:20:42,070 If you don't want to look, look down or look the other way. 311 00:20:42,070 --> 00:20:45,910 I'm going to show you a child that has retinoblastoma 312 00:20:45,910 --> 00:20:47,690 and what it looks like. 313 00:20:47,690 --> 00:20:51,820 So it's going to appear right now. 314 00:20:51,820 --> 00:20:54,880 So this is an individual with retinoblastoma. 315 00:20:54,880 --> 00:20:58,150 You can see that there's something inside the eye, 316 00:20:58,150 --> 00:21:00,040 growing in the back of it. 317 00:21:00,040 --> 00:21:03,280 And to give you a better picture of what is happening, 318 00:21:03,280 --> 00:21:06,880 this is now a cross section through a normal eye. 319 00:21:06,880 --> 00:21:10,420 This is a cartoon of the normal eye. 320 00:21:10,420 --> 00:21:13,420 And individuals with retinoblastoma 321 00:21:13,420 --> 00:21:16,510 have a growth in the back of the eye. 322 00:21:16,510 --> 00:21:18,070 From the retinal tissue you can see 323 00:21:18,070 --> 00:21:22,900 this huge tumor that's present in the back of this eye. 324 00:21:22,900 --> 00:21:26,260 So this disease involves the formation 325 00:21:26,260 --> 00:21:28,510 of these tumors in the eye that originate 326 00:21:28,510 --> 00:21:29,680 from the retinal tissue. 327 00:21:33,325 --> 00:21:33,825 All right. 328 00:21:36,960 --> 00:21:41,190 So this disease results - this is a tumor suppressor. 329 00:21:41,190 --> 00:21:44,550 It's a loss of function in the retinoblastoma. 330 00:21:44,550 --> 00:21:49,995 So there's a defect in the retinoblastoma gene. 331 00:21:53,560 --> 00:21:55,680 But this disease of retinoblastoma 332 00:21:55,680 --> 00:21:58,470 manifests itself in different ways. 333 00:21:58,470 --> 00:22:01,180 So there are different forms of the disease 334 00:22:01,180 --> 00:22:04,270 and I'll tell you how they're different right now. 335 00:22:04,270 --> 00:22:06,870 So there are two forms of the disease. 336 00:22:06,870 --> 00:22:10,050 The first, it's called sporadic. 337 00:22:16,740 --> 00:22:19,290 And it's called sporadic because this 338 00:22:19,290 --> 00:22:23,370 is a form of the disease that arises in families that 339 00:22:23,370 --> 00:22:26,610 have no history of the disease. 340 00:22:26,610 --> 00:22:34,380 So the sporadic form, the family has no history of the disease. 341 00:22:38,190 --> 00:22:43,210 And this disease presents in a certain way. 342 00:22:43,210 --> 00:22:48,780 The first is it is what is known as unilateral, meaning usually 343 00:22:48,780 --> 00:22:51,420 only one eye is affected. 344 00:22:51,420 --> 00:22:53,610 So it usually involves only one eye. 345 00:22:57,630 --> 00:23:02,670 And this disease can be treated in children. 346 00:23:02,670 --> 00:23:06,830 And if the sporadic form of the disease 347 00:23:06,830 --> 00:23:11,790 is treated in the child, then later on in life 348 00:23:11,790 --> 00:23:14,700 that individual does not have an increased risk 349 00:23:14,700 --> 00:23:16,980 of getting further tumors. 350 00:23:16,980 --> 00:23:23,740 So there's no increased risk of cancer later in life. 351 00:23:23,740 --> 00:23:27,450 For example, in a different organ. 352 00:23:27,450 --> 00:23:29,160 So this is one form of the disease. 353 00:23:32,050 --> 00:23:35,160 The other form of the disease is called familial. 354 00:23:39,760 --> 00:23:42,600 And as the name implies, familial 355 00:23:42,600 --> 00:23:46,380 means that the disease runs in the family. 356 00:23:46,380 --> 00:23:50,820 So what familial means is there's some inheritance. 357 00:23:50,820 --> 00:23:54,780 There's an inherited form of the disease. 358 00:23:54,780 --> 00:23:56,640 And the familial form of the disease 359 00:23:56,640 --> 00:23:59,790 can be distinguished from the sporadic form 360 00:23:59,790 --> 00:24:02,260 because it presents differently. 361 00:24:02,260 --> 00:24:04,740 The way the familial form presents 362 00:24:04,740 --> 00:24:11,250 is it's often bilateral, meaning that both eyes become affected. 363 00:24:11,250 --> 00:24:12,720 So it affects both eyes. 364 00:24:15,900 --> 00:24:20,370 And also in individuals with the familial form, 365 00:24:20,370 --> 00:24:23,010 even when they're cured from the eye tumors, 366 00:24:23,010 --> 00:24:26,970 they have a higher risk of getting other tumors 367 00:24:26,970 --> 00:24:30,210 in other organs of their body later on in life. 368 00:24:30,210 --> 00:24:34,590 So in this case, there is later an increased risk 369 00:24:34,590 --> 00:24:39,375 of cancer in other organs. 370 00:24:47,540 --> 00:24:50,440 So this is an example of a familial form 371 00:24:50,440 --> 00:24:54,670 of retinoblastoma, where affected individuals here 372 00:24:54,670 --> 00:24:57,130 are colored in green. 373 00:24:57,130 --> 00:25:01,270 So what would you say the inheritance pattern is 374 00:25:01,270 --> 00:25:03,100 for this particular phenotype? 375 00:25:13,520 --> 00:25:14,938 Carmen? 376 00:25:14,938 --> 00:25:17,360 CARMEN: Autosomal recessive. 377 00:25:17,360 --> 00:25:20,030 PROFESSOR: Why do you say autosomal recessive? 378 00:25:20,030 --> 00:25:21,598 Can you explain your logic? 379 00:25:21,598 --> 00:25:22,140 CARMEN: Yeah. 380 00:25:22,140 --> 00:25:30,333 It looks [INAUDIBLE] are affected regardless of-- 381 00:25:30,333 --> 00:25:32,625 with colorblindness it was always the sons that got it. 382 00:25:32,625 --> 00:25:35,250 [INAUDIBLE] getting it as well. 383 00:25:35,250 --> 00:25:39,050 But you can see some generations where neither parent 384 00:25:39,050 --> 00:25:41,077 had retinoblastoma. 385 00:25:43,880 --> 00:25:46,100 PROFESSOR: So Carmen's exactly right. 386 00:25:46,100 --> 00:25:49,400 And she's saying that both males and females are getting it, 387 00:25:49,400 --> 00:25:53,240 so it looks like that would argue that it's not 388 00:25:53,240 --> 00:25:56,330 sex linked, but autosomal. 389 00:25:56,330 --> 00:26:00,940 So it looks autosomal. 390 00:26:00,940 --> 00:26:02,630 And why do you say recessive? 391 00:26:02,630 --> 00:26:05,504 Can you explain your logic there? 392 00:26:05,504 --> 00:26:07,894 CARMEN: The third from the left. 393 00:26:07,894 --> 00:26:09,510 The one that has an arrow on it. 394 00:26:09,510 --> 00:26:12,558 Both parents are affected [INAUDIBLE].. 395 00:26:12,558 --> 00:26:14,516 The only way that's possible for their children 396 00:26:14,516 --> 00:26:18,170 to get the recessive gene. 397 00:26:18,170 --> 00:26:21,110 PROFESSOR: So Carmen is exactly right. 398 00:26:21,110 --> 00:26:23,910 She's looking at this individual here. 399 00:26:23,910 --> 00:26:25,880 And in this case, this individual 400 00:26:25,880 --> 00:26:28,370 was not affected with the disease, 401 00:26:28,370 --> 00:26:33,805 but passed on the disease to their daughters. 402 00:26:33,805 --> 00:26:37,880 Now I think one thing. 403 00:26:37,880 --> 00:26:39,980 This is an exception to the rule. 404 00:26:39,980 --> 00:26:43,310 What you see in pretty much all the other cases is 405 00:26:43,310 --> 00:26:47,030 that individuals in this generation in the middle 406 00:26:47,030 --> 00:26:51,950 here do have the disease, and they pass on the disease 407 00:26:51,950 --> 00:26:53,760 to the next generation. 408 00:26:53,760 --> 00:27:00,380 So because I'm seeing the disease in all generations, 409 00:27:00,380 --> 00:27:06,260 I would say that this is likely to be autosomal dominant. 410 00:27:06,260 --> 00:27:08,390 And Carmen picked up on something 411 00:27:08,390 --> 00:27:10,370 that I want to come to. 412 00:27:10,370 --> 00:27:12,890 It so happens that this individual 413 00:27:12,890 --> 00:27:18,920 was not affected by the disease, but still clearly carried 414 00:27:18,920 --> 00:27:20,430 a disease allele. 415 00:27:20,430 --> 00:27:24,740 And I'm going to talk about why this is an exception 416 00:27:24,740 --> 00:27:28,640 and why this is still an autosomal dominant inheritance 417 00:27:28,640 --> 00:27:30,570 pattern. 418 00:27:30,570 --> 00:27:39,690 But if we take it that this is an autosomal dominant disease, 419 00:27:39,690 --> 00:27:43,070 it's kind of counter intuitive, at least to me, and maybe 420 00:27:43,070 --> 00:27:47,600 to you, because I just told you that tumor suppressors result 421 00:27:47,600 --> 00:27:51,680 from a loss of function of the gene. 422 00:27:51,680 --> 00:27:55,580 And we're used to seeing loss of function mutations 423 00:27:55,580 --> 00:27:58,460 being recessive. 424 00:27:58,460 --> 00:28:02,480 And actually, at the cellular level, it's true. 425 00:28:02,480 --> 00:28:05,480 The cancer is recessive. 426 00:28:05,480 --> 00:28:07,310 But in this case, what you see is 427 00:28:07,310 --> 00:28:11,810 that, at the organismal level, the inheritance pattern 428 00:28:11,810 --> 00:28:15,500 actually acts as a dominant phenotype. 429 00:28:15,500 --> 00:28:18,320 So there's kind of a difference between the inheritance 430 00:28:18,320 --> 00:28:23,780 pattern at the cell level and at the organismal level. 431 00:28:23,780 --> 00:28:26,030 And I want to tell you why that is 432 00:28:26,030 --> 00:28:29,450 because I think it's important for understanding 433 00:28:29,450 --> 00:28:32,910 the risk to cancer. 434 00:28:32,910 --> 00:28:42,230 And so what's inherited is not the full blown disease. 435 00:28:42,230 --> 00:28:46,490 What's inherited in the case of retinoblastoma 436 00:28:46,490 --> 00:28:51,950 and many other cancers is a predisposition to the disease. 437 00:28:51,950 --> 00:29:07,865 So what is inherited is the predisposition to the disease. 438 00:29:11,330 --> 00:29:16,190 And that's because if we look at, let's 439 00:29:16,190 --> 00:29:21,890 consider the top male up here. 440 00:29:21,890 --> 00:29:27,680 If that male is heterozygous for the Rb gene, 441 00:29:27,680 --> 00:29:32,980 then he can have a gamete, which is Rb-, 442 00:29:32,980 --> 00:29:36,440 so lacking a functional copy of the Rb gene. 443 00:29:36,440 --> 00:29:43,100 And he married an individual without a disease a label, 444 00:29:43,100 --> 00:29:47,960 so she's going to just make Rb+ gametes. 445 00:29:47,960 --> 00:29:53,360 And if they have children and one of the children 446 00:29:53,360 --> 00:29:59,450 gets a gamete that is derived from Rb- allele, 447 00:29:59,450 --> 00:30:03,320 then you get an individual in the zygote here 448 00:30:03,320 --> 00:30:07,640 which has one functional copy of the Rb gene 449 00:30:07,640 --> 00:30:10,550 and one mutant copy of the Rb gene. 450 00:30:13,500 --> 00:30:15,690 So that's the egg, and then that egg 451 00:30:15,690 --> 00:30:17,250 is going to develop and give rise 452 00:30:17,250 --> 00:30:19,660 to all of the cells of the body. 453 00:30:19,660 --> 00:30:23,700 And so in this case, all of the somatic cells 454 00:30:23,700 --> 00:30:25,960 from this individual are going to be 455 00:30:25,960 --> 00:30:28,860 heterozygous for the Rb gene. 456 00:30:28,860 --> 00:30:44,390 So all somatic cells are heterozygous for Rb. 457 00:30:44,390 --> 00:30:47,100 So they're Rb+ over Rb-. 458 00:30:49,640 --> 00:30:52,590 And the effect of that is, is it means 459 00:30:52,590 --> 00:30:56,160 that each of the cells in this individual 460 00:30:56,160 --> 00:31:00,120 are only one step away or one mutation away 461 00:31:00,120 --> 00:31:02,535 from lacking both copies of Rb. 462 00:31:06,390 --> 00:31:09,210 So by being heterozygous, it means 463 00:31:09,210 --> 00:31:20,670 that all cells in the individual are just one mutation or step 464 00:31:20,670 --> 00:31:21,770 from losing Rb. 465 00:31:28,230 --> 00:31:31,800 And so the inheritance pattern, what you're looking at 466 00:31:31,800 --> 00:31:35,130 is the predisposition to the disease. 467 00:31:35,130 --> 00:31:37,290 And the predisposition doesn't mean 468 00:31:37,290 --> 00:31:40,860 that a person is guaranteed to get the disease. 469 00:31:40,860 --> 00:31:43,800 And that's illustrated in this family tree, right? 470 00:31:43,800 --> 00:31:48,330 There was an individual here, this male here with the arrow, 471 00:31:48,330 --> 00:31:51,300 who clearly was a carrier for the disease 472 00:31:51,300 --> 00:31:54,570 because he passed on the disease to his children, 473 00:31:54,570 --> 00:31:59,490 but who himself never actually was affected by the disease. 474 00:31:59,490 --> 00:32:01,690 So because it's a predisposition, 475 00:32:01,690 --> 00:32:03,600 it doesn't mean there's a guarantee. 476 00:32:03,600 --> 00:32:09,690 That if you are heterozygous for Rb, 477 00:32:09,690 --> 00:32:11,370 there's not a guarantee that you're 478 00:32:11,370 --> 00:32:13,860 going to have the disease, but you are 479 00:32:13,860 --> 00:32:15,450 going to be predisposed to it. 480 00:32:15,450 --> 00:32:18,910 And in the case of Rb, more often than not, 481 00:32:18,910 --> 00:32:21,330 if you lack one functional copy of Rb 482 00:32:21,330 --> 00:32:24,010 and are heterozygous for all of your cells, 483 00:32:24,010 --> 00:32:29,072 then you're going to be affected by the disease. 484 00:32:29,072 --> 00:32:30,280 Does that make sense, Carmen? 485 00:32:30,280 --> 00:32:31,140 CARMEN: Yeah. 486 00:32:31,140 --> 00:32:31,723 PROFESSOR: OK. 487 00:32:35,220 --> 00:32:36,210 Yeah, Jeremy? 488 00:32:36,210 --> 00:32:39,270 JEREMY: [INAUDIBLE] people who are 489 00:32:39,270 --> 00:32:43,000 heterozygous and homozygous for the disease are affected by it. 490 00:32:43,000 --> 00:32:47,370 PROFESSOR: Well, actually, if you are homozygous from Rb, 491 00:32:47,370 --> 00:32:49,900 the individual would probably not be born. 492 00:32:49,900 --> 00:32:51,090 Yeah. 493 00:32:51,090 --> 00:32:55,680 So I think it would be impossible to be heterozygous 494 00:32:55,680 --> 00:32:56,790 for Rb. 495 00:32:56,790 --> 00:32:58,050 Yeah. 496 00:32:58,050 --> 00:33:01,800 So really what you're inheriting here is that predisposition. 497 00:33:01,800 --> 00:33:06,540 And because the predisposition just requires heterozygosity, 498 00:33:06,540 --> 00:33:09,990 it manifests itself like a dominant phenotype. 499 00:33:09,990 --> 00:33:13,950 Because you only need to inherit one allele 500 00:33:13,950 --> 00:33:17,820 that's mutant in order to be predisposed to get the disease. 501 00:33:17,820 --> 00:33:21,210 So that that's why it appears at the organismal level 502 00:33:21,210 --> 00:33:27,900 to be a dominantly inherited phenotype. 503 00:33:27,900 --> 00:33:31,350 But then to get the disease, you need 504 00:33:31,350 --> 00:33:34,680 to lose a second copy of the gene. 505 00:33:34,680 --> 00:33:36,990 And so for the sporadic form of the disease, 506 00:33:36,990 --> 00:33:39,480 so we just talked about hereditary or familial 507 00:33:39,480 --> 00:33:42,690 retinoblastoma, all of the cells of the individual 508 00:33:42,690 --> 00:33:45,090 will start out being heterozygous 509 00:33:45,090 --> 00:33:47,940 and then some of them will lose, what 510 00:33:47,940 --> 00:33:51,750 is known as lose heterozygosity, and become homozygous mutant 511 00:33:51,750 --> 00:33:54,330 in a particular tissue. 512 00:33:54,330 --> 00:33:56,800 And that would be the tumor tissue. 513 00:33:56,800 --> 00:33:58,470 So what are some ways that there could 514 00:33:58,470 --> 00:34:01,200 be this loss of heterozygosity? 515 00:34:01,200 --> 00:34:04,410 Can you guys come up with some possible ways to do that? 516 00:34:04,410 --> 00:34:05,601 Heterozygosity. 517 00:34:09,780 --> 00:34:13,230 How might a cell lose that second copy of Rb? 518 00:34:16,060 --> 00:34:17,949 What are some potential mechanisms 519 00:34:17,949 --> 00:34:21,949 that you could lose it? 520 00:34:21,949 --> 00:34:22,449 Rachel? 521 00:34:22,449 --> 00:34:23,620 RACHEL: Point mutation. 522 00:34:23,620 --> 00:34:27,010 PROFESSOR: It could be a point mutation, exactly right. 523 00:34:27,010 --> 00:34:31,354 So one way would be point mutation in Rb. 524 00:34:31,354 --> 00:34:31,854 Other ideas? 525 00:34:34,920 --> 00:34:35,790 Yeah, Patricia? 526 00:34:35,790 --> 00:34:40,725 PATRICIA: There isn't proper separation during mitosis 527 00:34:40,725 --> 00:34:44,100 and you only get one copy. 528 00:34:44,100 --> 00:34:46,590 PROFESSOR: So if you lose a chromosome, right? 529 00:34:46,590 --> 00:34:48,600 So if you guys remember back, remember 530 00:34:48,600 --> 00:34:53,550 way back when we are all young men and women in early October. 531 00:34:53,550 --> 00:34:57,030 We did the whole demonstration with mitosis 532 00:34:57,030 --> 00:35:01,050 and we had a case where we had two good friends 533 00:35:01,050 --> 00:35:02,820 across the metaphase plate. 534 00:35:02,820 --> 00:35:09,000 And that brought both sister chromatids off to one side. 535 00:35:09,000 --> 00:35:12,540 That would result in loss of a chromosome. 536 00:35:12,540 --> 00:35:14,760 And in this case, if you have a division 537 00:35:14,760 --> 00:35:18,510 and you lose the wild type copy of Rb, 538 00:35:18,510 --> 00:35:20,737 if you lose that entire chromosome, 539 00:35:20,737 --> 00:35:22,320 then you're going to be left with only 540 00:35:22,320 --> 00:35:25,590 the mutant copy of the Rb. 541 00:35:25,590 --> 00:35:28,920 So another mechanism would be chromosome loss. 542 00:35:34,040 --> 00:35:37,070 Where the chromosome that's lost is the chromosome with the wild 543 00:35:37,070 --> 00:35:41,150 type Rb+ allele. 544 00:35:41,150 --> 00:35:43,640 Any other ideas as to how you might 545 00:35:43,640 --> 00:35:46,575 lose the second functional copy of Rb? 546 00:35:51,770 --> 00:35:52,399 Yeah, Miles. 547 00:35:52,399 --> 00:35:53,899 MILES: I'm not sure if it completely 548 00:35:53,899 --> 00:35:56,320 falls under point mutation, but overall DNA damage? 549 00:35:56,320 --> 00:35:58,260 PROFESSOR: Yeah, can have DNA damage. 550 00:35:58,260 --> 00:35:59,970 You can have a deletion that deletes 551 00:35:59,970 --> 00:36:03,600 the entire region of the chromosome that contains Rb. 552 00:36:03,600 --> 00:36:06,840 There could be even chromosomal abnormalities, 553 00:36:06,840 --> 00:36:10,470 like translocation, that somehow delete Rb. 554 00:36:10,470 --> 00:36:12,790 So I'll just say deletion for now. 555 00:36:17,040 --> 00:36:20,180 Any others? 556 00:36:20,180 --> 00:36:21,770 Can anyone think of something that 557 00:36:21,770 --> 00:36:24,620 wouldn't be necessarily a genetic change, but more 558 00:36:24,620 --> 00:36:27,830 of an epigenetic change, so to speak? 559 00:36:33,940 --> 00:36:34,956 Yeah, Natalie. 560 00:36:34,956 --> 00:36:37,750 NATALIE: [INAUDIBLE] mutagenized? 561 00:36:37,750 --> 00:36:40,840 PROFESSOR: Being mutagenized? 562 00:36:40,840 --> 00:36:44,380 NATALIE: Exposed to rays of something. 563 00:36:44,380 --> 00:36:45,880 PROFESSOR: But then that would cause 564 00:36:45,880 --> 00:36:49,060 a mutation, which might fall into one of these three classes 565 00:36:49,060 --> 00:36:49,930 here. 566 00:36:49,930 --> 00:36:56,660 What about without being mutagenized, non mutagenic. 567 00:36:56,660 --> 00:36:57,850 Yeah, Maxwell. 568 00:36:57,850 --> 00:36:59,933 MAXWELL: Are there any other environmental factors 569 00:36:59,933 --> 00:37:01,203 that control expression of Rb? 570 00:37:01,203 --> 00:37:01,870 PROFESSOR: Yeah. 571 00:37:01,870 --> 00:37:04,480 So Maxwell's saying, what else would control 572 00:37:04,480 --> 00:37:07,930 the expression of the Rb gene? 573 00:37:07,930 --> 00:37:11,170 What if you had an effect that would basically 574 00:37:11,170 --> 00:37:15,946 cause that functional copy of Rb to be not expressed? 575 00:37:15,946 --> 00:37:20,980 And so this is another way that you can lose heterozygosity, 576 00:37:20,980 --> 00:37:29,390 as you have repression of transcription. 577 00:37:29,390 --> 00:37:31,390 And I'm not going to go through the nitty gritty 578 00:37:31,390 --> 00:37:35,620 of the details, but one way in which genes are regulated 579 00:37:35,620 --> 00:37:41,800 is by modification of DNA by chemical modifications, 580 00:37:41,800 --> 00:37:43,090 like methylation. 581 00:37:43,090 --> 00:37:46,930 And so promoter methylation is a mechanism 582 00:37:46,930 --> 00:37:49,870 that causes repression of gene expression. 583 00:37:49,870 --> 00:37:53,320 And in many cases in cancer, the functional copy 584 00:37:53,320 --> 00:37:55,900 of a tumor suppressor will basically 585 00:37:55,900 --> 00:37:59,650 be lost by promoter methylation, so that you no longer express 586 00:37:59,650 --> 00:38:01,990 that gene in that cancer cell. 587 00:38:01,990 --> 00:38:06,850 And therefore, the cancer cell has a cancer phenotype. 588 00:38:10,320 --> 00:38:12,850 Any questions on Rb before I move on? 589 00:38:16,270 --> 00:38:20,170 Everyone understands why retinoblastoma 590 00:38:20,170 --> 00:38:22,540 is dominant at the organismal level, 591 00:38:22,540 --> 00:38:25,222 yet recessive at the cell level? 592 00:38:25,222 --> 00:38:26,305 That's an important point. 593 00:38:29,020 --> 00:38:34,300 The concept behind that is also the same for BRCA1 594 00:38:34,300 --> 00:38:38,680 and other tumor suppressors like p53 and APC, 595 00:38:38,680 --> 00:38:40,120 which you'll see in just a minute. 596 00:38:45,950 --> 00:38:46,450 All right. 597 00:38:46,450 --> 00:38:48,790 So now I want to move up kind of from thinking 598 00:38:48,790 --> 00:38:52,540 about the mechanism of cancer at the level of a cell 599 00:38:52,540 --> 00:38:55,670 and let's think about it at the level of a tissue. 600 00:38:55,670 --> 00:38:58,060 And as an example, I want to use colon cancer. 601 00:39:01,900 --> 00:39:04,090 And you'll recall from Wednesday, 602 00:39:04,090 --> 00:39:07,810 I talked about the intestine as a system. 603 00:39:07,810 --> 00:39:09,820 And the way it works is pretty much the same 604 00:39:09,820 --> 00:39:12,520 for both the small and the large intestine. 605 00:39:12,520 --> 00:39:15,670 It just happens in the large intestine or the colon, 606 00:39:15,670 --> 00:39:20,980 you don't have villi, but you do still have these crypts. 607 00:39:20,980 --> 00:39:23,110 So that would be what a colon would 608 00:39:23,110 --> 00:39:26,110 look like, more or less, or at least one crypt of a colon. 609 00:39:31,590 --> 00:39:34,160 And remember, at the base of the crypt, 610 00:39:34,160 --> 00:39:37,010 there was this specialized compartment, 611 00:39:37,010 --> 00:39:40,820 which was the stem cell niche. 612 00:39:40,820 --> 00:39:43,730 And this is where renewal was happening. 613 00:39:43,730 --> 00:39:48,410 And renewal and cell division down at the base of the crypt 614 00:39:48,410 --> 00:39:51,500 then results in this conveyor belt-like movement up 615 00:39:51,500 --> 00:39:55,820 to the region of the tissue near the lumen, where cells 616 00:39:55,820 --> 00:40:00,290 are shut off into the lumen. 617 00:40:00,290 --> 00:40:08,090 So what might be one barrier to cancer 618 00:40:08,090 --> 00:40:10,730 that has to be overcome in order for a tumor 619 00:40:10,730 --> 00:40:12,920 to form in this organ? 620 00:40:12,920 --> 00:40:13,500 Yeah, Miles. 621 00:40:13,500 --> 00:40:17,720 MILES: You know the diagram [INAUDIBLE] cells. 622 00:40:17,720 --> 00:40:22,471 So the one part that [INAUDIBLE] would be [INAUDIBLE].. 623 00:40:22,471 --> 00:40:24,596 It's when the cells get [INAUDIBLE] into the lumen. 624 00:40:24,596 --> 00:40:27,580 [INAUDIBLE] system anymore. 625 00:40:27,580 --> 00:40:33,440 So if cancer cells, [INAUDIBLE] just never shed off [INAUDIBLE] 626 00:40:33,440 --> 00:40:37,447 keep [INAUDIBLE] and it would be just moved along the intestine 627 00:40:37,447 --> 00:40:38,030 and never die. 628 00:40:38,030 --> 00:40:43,180 [INAUDIBLE] undying cells that won't ever shed. 629 00:40:43,180 --> 00:40:45,260 PROFESSOR: Yeah, so what Miles is saying 630 00:40:45,260 --> 00:40:49,170 is that these cells are going to move up and get shed off. 631 00:40:49,170 --> 00:40:53,780 And so if you have a mutation, either an oncogenic mutation 632 00:40:53,780 --> 00:40:57,620 or loss of tumor suppressors, if it goes up, and sheds, 633 00:40:57,620 --> 00:41:00,410 and is removed from the organ, it doesn't matter. 634 00:41:00,410 --> 00:41:03,320 That cell is not going to be able to form a tumor. 635 00:41:03,320 --> 00:41:06,740 So one thing that has to happen for a cell 636 00:41:06,740 --> 00:41:10,880 to form a tumor in this system is this treadmill 637 00:41:10,880 --> 00:41:16,220 has to be blocked, such that cells are no longer exiting 638 00:41:16,220 --> 00:41:18,260 the organ, so that you have a cell 639 00:41:18,260 --> 00:41:19,820 actually stay in the organ that would 640 00:41:19,820 --> 00:41:22,640 be able to accumulate additional mutations 641 00:41:22,640 --> 00:41:27,370 and undergo tumorigenesis. 642 00:41:27,370 --> 00:41:31,120 And this is what happens because, as we 643 00:41:31,120 --> 00:41:35,980 know in colon cancer, one of the first steps in colon cancer 644 00:41:35,980 --> 00:41:42,070 is disregulation of the signaling that really regulates 645 00:41:42,070 --> 00:41:47,380 this movement of cells and the homeostasis of the tissue. 646 00:41:47,380 --> 00:41:50,860 So step one here. 647 00:41:50,860 --> 00:41:56,830 Step one is to dysregulate the main signaling pathway that's 648 00:41:56,830 --> 00:41:59,568 involved in this, which is Wnt signaling. 649 00:42:04,150 --> 00:42:07,390 And so another famous tumor suppressor 650 00:42:07,390 --> 00:42:11,800 is called the APC gene. 651 00:42:11,800 --> 00:42:13,180 This is a tumor suppressor. 652 00:42:20,740 --> 00:42:27,850 And this APC gene is associated with another familial form 653 00:42:27,850 --> 00:42:28,900 of cancer. 654 00:42:28,900 --> 00:42:32,650 In this case, it's familial adenomatous polyposis. 655 00:42:32,650 --> 00:42:34,750 And so this is a normal colon. 656 00:42:34,750 --> 00:42:37,900 Normally your colon has a smooth surface. 657 00:42:37,900 --> 00:42:39,400 It's basically smooth here. 658 00:42:39,400 --> 00:42:41,380 I mean, there are some folds, but I'm not sure 659 00:42:41,380 --> 00:42:45,460 that that's not an effect of having this dissected out 660 00:42:45,460 --> 00:42:46,830 of the organism. 661 00:42:46,830 --> 00:42:50,140 But in individuals with familial adenomatous 662 00:42:50,140 --> 00:42:54,220 polyposis, what happens is that the colon 663 00:42:54,220 --> 00:42:56,830 forms many of these polyps, which 664 00:42:56,830 --> 00:43:00,740 are benign cancer outgrowths. 665 00:43:00,740 --> 00:43:02,290 But you see all these polyps here 666 00:43:02,290 --> 00:43:05,080 and you see how very different the morphology of the colon 667 00:43:05,080 --> 00:43:09,730 is from a normal individual and an individual that has 668 00:43:09,730 --> 00:43:13,780 familial adenomatous polyposis. 669 00:43:13,780 --> 00:43:19,540 So the formation of a polyp is kind of equivalent to something 670 00:43:19,540 --> 00:43:20,080 like this. 671 00:43:20,080 --> 00:43:22,630 It's not invasive yet. 672 00:43:22,630 --> 00:43:24,850 It would be known as benign. 673 00:43:24,850 --> 00:43:26,530 But you can see that there is clearly 674 00:43:26,530 --> 00:43:30,010 a dysregulation in how this tissue is 675 00:43:30,010 --> 00:43:33,670 behaving because you get all of these polyps forming. 676 00:43:33,670 --> 00:43:37,240 And it's thought that frank carcinoma then 677 00:43:37,240 --> 00:43:41,740 results from cells in one of these polyps 678 00:43:41,740 --> 00:43:44,140 accumulating additional mutations that 679 00:43:44,140 --> 00:43:46,510 then cause the cancer to progress 680 00:43:46,510 --> 00:43:49,600 to a more malignant stage. 681 00:43:49,600 --> 00:43:54,920 So I told you that APC a tumor suppressor. 682 00:43:54,920 --> 00:43:58,720 And in this case, this tumor suppressor 683 00:43:58,720 --> 00:44:02,650 is associated with this disease right here. 684 00:44:02,650 --> 00:44:06,070 And I showed you the Wnt pathway last week. 685 00:44:06,070 --> 00:44:09,190 And I went through it quickly, but you 686 00:44:09,190 --> 00:44:11,620 notice this central protein right here 687 00:44:11,620 --> 00:44:15,130 in this destruction complex, that's APC. 688 00:44:15,130 --> 00:44:19,380 APC stands for adenomatous polyposis coli. 689 00:44:19,380 --> 00:44:21,290 I will write that down. 690 00:44:21,290 --> 00:44:30,510 So adenomatous polyposis coli. 691 00:44:35,500 --> 00:44:40,060 And what APC does, as represented in that slide 692 00:44:40,060 --> 00:44:44,350 above, is it's part of this destruction complex that 693 00:44:44,350 --> 00:44:48,460 destroys beta-catenin, which is the downstream step of Wnt 694 00:44:48,460 --> 00:44:49,620 signaling. 695 00:44:49,620 --> 00:44:54,940 So the wild type function of APC is to basically inhibit 696 00:44:54,940 --> 00:44:59,680 beta-catenin, which then is mediating 697 00:44:59,680 --> 00:45:01,673 the effects of Wnt signaling. 698 00:45:07,630 --> 00:45:11,650 So you can think of APC as one of the genes that's 699 00:45:11,650 --> 00:45:15,440 the brake on Wnt signaling. 700 00:45:15,440 --> 00:45:17,530 And normally, it's regulated by Wnt. 701 00:45:20,470 --> 00:45:25,600 So Wnt would normally inhibit APC. 702 00:45:25,600 --> 00:45:29,380 But if you just delete APC in a cell, 703 00:45:29,380 --> 00:45:32,480 then it's like the cell is seeing Wnt all the time. 704 00:45:32,480 --> 00:45:36,340 So by deleting APC, you get a constitutive activation 705 00:45:36,340 --> 00:45:40,090 of beta-catenin and you get constitutive activation 706 00:45:40,090 --> 00:45:43,240 of Wnt signaling. 707 00:45:43,240 --> 00:45:48,340 So if the organism starts out being heterozygous for APC, 708 00:45:48,340 --> 00:45:52,360 then there is a high probability that another mutation 709 00:45:52,360 --> 00:45:56,400 will take out the wild type function of APC 710 00:45:56,400 --> 00:45:58,700 or the wild type allele of it. 711 00:45:58,700 --> 00:46:00,460 And when you take out that allele, 712 00:46:00,460 --> 00:46:02,680 now you all of the sudden start having these cells 713 00:46:02,680 --> 00:46:07,870 that it's like they are always in Wnt, 714 00:46:07,870 --> 00:46:09,970 even though they're not. 715 00:46:09,970 --> 00:46:13,990 And so if you constitutively activate Wnt signaling, 716 00:46:13,990 --> 00:46:15,940 what that does is it prevents the cells 717 00:46:15,940 --> 00:46:18,880 from leaving the organ. 718 00:46:18,880 --> 00:46:20,530 So they're stuck. 719 00:46:20,530 --> 00:46:24,090 So normally in a normal colon, cells 720 00:46:24,090 --> 00:46:26,750 that are renewed at the bottom of the crypt, they move up, 721 00:46:26,750 --> 00:46:28,520 and then they're shed into the lumen. 722 00:46:28,520 --> 00:46:33,920 But in an APC mutant, the cells are constantly 723 00:46:33,920 --> 00:46:36,090 feeling like they're getting Wnt signal, 724 00:46:36,090 --> 00:46:38,330 and so they stay in the colon. 725 00:46:38,330 --> 00:46:42,560 And that allows them to accumulate further mutations. 726 00:46:42,560 --> 00:46:47,540 So step one in colon cancer is to dysregulate Wnt signaling, 727 00:46:47,540 --> 00:46:50,660 and that really disrupts the whole tissue homeostatic 728 00:46:50,660 --> 00:46:53,540 mechanism of the intestine. 729 00:46:53,540 --> 00:46:59,240 Then there would be further steps, at least three 730 00:46:59,240 --> 00:47:01,040 usually in colon cancer. 731 00:47:01,040 --> 00:47:04,520 And that would involve mutations, oncogenic mutations, 732 00:47:04,520 --> 00:47:06,320 loss of tumor suppressors. 733 00:47:06,320 --> 00:47:09,230 And that would just cause the cells 734 00:47:09,230 --> 00:47:13,910 to get more and more oncogenic and more and more transformed. 735 00:47:13,910 --> 00:47:15,980 And eventually, they can become invasive, 736 00:47:15,980 --> 00:47:18,110 and we'll talk about what happens when cells 737 00:47:18,110 --> 00:47:20,840 become invasive next week. 738 00:47:23,810 --> 00:47:25,910 So I wanted to end today's lecture 739 00:47:25,910 --> 00:47:33,020 by talking about targeted treatments for cancer 740 00:47:33,020 --> 00:47:35,570 just to see how they interface with the mechanisms 741 00:47:35,570 --> 00:47:37,070 that we've discussed. 742 00:47:37,070 --> 00:47:41,930 And of course, some of the primary ways to treat cancer 743 00:47:41,930 --> 00:47:45,920 are through surgery and also chemotherapy. 744 00:47:45,920 --> 00:47:53,900 But there are also more directed ways to target cancer. 745 00:47:53,900 --> 00:47:57,920 And because time's up, well, I have one minute. 746 00:47:57,920 --> 00:48:00,170 I'll tell you about the first one. 747 00:48:00,170 --> 00:48:03,170 And then if I have more to go, I'll 748 00:48:03,170 --> 00:48:07,348 start with that in next week's lecture. 749 00:48:07,348 --> 00:48:09,140 So the first one I wanted to tell you about 750 00:48:09,140 --> 00:48:14,390 is this disease, chronic myelogenous leukemia, 751 00:48:14,390 --> 00:48:18,170 which involves activation of the ABL gene. 752 00:48:18,170 --> 00:48:19,850 And it's activated, in this case, 753 00:48:19,850 --> 00:48:24,090 by a translocation between two different chromosomes. 754 00:48:24,090 --> 00:48:25,670 So this is chromosome 22. 755 00:48:25,670 --> 00:48:27,680 This is chromosome 9. 756 00:48:27,680 --> 00:48:32,480 And in many patients with chronic myelogenous leukemia, 757 00:48:32,480 --> 00:48:37,940 a large part of chromosome 22 is translocated onto chromosome 9, 758 00:48:37,940 --> 00:48:42,110 and a little bit of chromosome 9 is attached to chromosome 2. 759 00:48:42,110 --> 00:48:46,760 And this translocation generates a gene fusion between the BCR 760 00:48:46,760 --> 00:48:48,220 gene and the ABL gene. 761 00:48:51,520 --> 00:48:56,090 And so ABL is a non receptor tyrosine kinase. 762 00:49:02,000 --> 00:49:04,940 So it's a tyrosine kinase that is 763 00:49:04,940 --> 00:49:08,070 present in the cytoplasm of the cell and promotes growth. 764 00:49:08,070 --> 00:49:09,470 So this is a proto-oncogene. 765 00:49:16,340 --> 00:49:21,260 And when ABL becomes hooked up to BDR, then 766 00:49:21,260 --> 00:49:25,343 this results in the constitutive activation of BCR ABL. 767 00:49:25,343 --> 00:49:27,260 So this is now a constitutively active kinase. 768 00:49:34,190 --> 00:49:39,140 Now when this was realized, then researchers 769 00:49:39,140 --> 00:49:42,110 started looking for small molecules that would inhibit 770 00:49:42,110 --> 00:49:45,200 the kinase activity of ABL. 771 00:49:45,200 --> 00:49:48,500 And the famous example is Gleevec. 772 00:49:48,500 --> 00:49:50,510 And this is a picture of Gleevec here. 773 00:49:50,510 --> 00:49:52,800 You can see it's a small molecule. 774 00:49:52,800 --> 00:49:54,890 And what Gleevec does is now this 775 00:49:54,890 --> 00:49:59,840 is a crystal structure of the ABL tyrosine kinase in green. 776 00:49:59,840 --> 00:50:02,690 And it has two lobes, an N terminal lobe, a C terminal 777 00:50:02,690 --> 00:50:04,910 lobe, like a lot of kinases. 778 00:50:04,910 --> 00:50:08,000 And what Gleevec does is to bind in the interface 779 00:50:08,000 --> 00:50:09,590 between these two lobes. 780 00:50:09,590 --> 00:50:13,580 And it locks this kinase in an inactive conformation, such 781 00:50:13,580 --> 00:50:17,150 that if cells see this Gleevec, then 782 00:50:17,150 --> 00:50:20,150 their ABL tyrosine kinase is inhibited. 783 00:50:20,150 --> 00:50:24,440 And this is the driver of chronic myelogenous leukemia. 784 00:50:24,440 --> 00:50:27,650 So Gleevec has been very effective in treating 785 00:50:27,650 --> 00:50:30,740 this type of leukemia and it results 786 00:50:30,740 --> 00:50:34,130 in a pretty good prognosis for patients. 787 00:50:34,130 --> 00:50:37,850 All right, so we'll talk about more therapies next Wednesday, 788 00:50:37,850 --> 00:50:40,540 but have a good holiday weekend.