Presentation on theme: "NOTES: CH 18 part 2 - The Molecular Biology of Cancer"— Presentation transcript:
1 NOTES: CH 18 part 2 - The Molecular Biology of Cancer
2 Certain genes normally regulate cell growth & division – the cell cycle. ● mutations that alter these genes in somatic cells can lead to cancer● mutations may be spontaneous or the result of exposure to a MUTAGEN / CARCINOGEN
3 GENES & CANCER:● ONCOGENES = cancer-causing genes, first found in certain retroviruses● subsequently, close counterparts have been found in the genomes of humans & other animals● PROTO-ONCOGENES = normal cellular genes that code for proteins that stimulate normal cell growth & division.
6 How Might a Proto-Oncogene Become an Oncogene? ● In general, an oncogene arises from a genetic change that leads to an INCREASE in either: the amount of the proto-oncogene’s protein product; the intrinsic activity of each protein molecule
8 The genetic changes that convert proto-oncogenes to oncogenes fall into 3 categories: 1) Movement of DNA within the genome;2) Amplification of a proto-oncogene;3) Point mutation in an oncogene (or one of its control elements).
9 1) Movement of DNA within the genome: ● chromosomes may break and then rejoin incorrectly, translocating fragments from 1 chromosome to another● a proto-oncogene may now lie adjacent to a more active promoter● or, an active promoter may move by transposition to the region just upstream of the proto-oncogene, increasing its expression
11 2) Amplification of a proto-oncogene : ● increases the # of copies of the gene in a cell through repeated gene duplication
12 3) Point mutation in a proto-oncogene (or a control element): ● changes the gene’s protein product to one that is more active or more resistant to degradation than the normal protein…● or could be a point mutation in the promoter of a gene, causing an increase in its expression;…all of these changes can lead to abnormal stimulation of the cell cycle and put the cell on the path to malignancy.
17 ● the changes considered thus far affect growth-stimulating proteins… ● however, changes in genes whose normal products INHIBIT cell division also contribute to cancer…● such genes are called: TUMOR-SUPPRESSOR GENES
18 Tumor-Suppressor Genes: ● the proteins encoded by these genesnormally help to prevent uncontrolled cellgrowth.● any mutation that decreases the normalactivity of a tumor-suppressor protein maycontribute to the onset of cancer(stimulates growth through the absence ofsuppression!)
20 Tumor-Suppressor Genes – What Do They Do? They may encode a protein that…● repairs damaged DNA (prevents cell fromaccumulating cancer-causing mutations)● controls the adhesion of cells to each other or toan extracellular matrix (proper cell anchorage iscrucial in normal tissues)● are components of cell-signaling pathways thatinhibit the cell cycle
23 ras proto-oncogene:● mutations in the ras gene are found in about 30% of human cancers● the product is the Ras protein● the Ras protein is a G protein that relays a growth signal from a growth factor receptor on the plasma membrane to a cascade of protein kinases
24 ras proto-oncogene:● the response: synthesis of a protein that stimulates the cell cycle● many ras oncogenes have a point mutation that leads to a hyperactive version of the Ras protein that signals on its own…● the outcome: excessive cell division!
26 p53 tumor-suppressor gene: ● mutations in the p53 gene are found in about 50% of human cancers● the product of the p53 gene is a protein that is transcription factor that promotes synthesis of growth-inhibiting proteins…● so, a mutation knocking out the p53 gene can lead to excessive cell growth & cancer● the p53 protein acts in several ways to prevent a cell from passing on mutations or damaged DNA:
28 p53 gene:● the p53 gene has been called the “guardian angel of the genome”…● once the p53 gene is activated – for example, by DNA damage – the p53 protein functions as an activator for several other genes…
29 p53 protein:(1) activates a gene (p21) whose product halts the cell cycle, allowing time for the cell to repair any damaged DNA;(2) can turn on genes directly involved in DNA repair;(3) Activates expression of a group of miRNAs, which in turn inhibit the cell cycle;(4) when DNA damage is irreparable, p53 activates “suicide” genes, whose protein products cause cell death by APOPTOSIS
31 p53 protein:● thus, p53 acts in several ways to prevent a cell from passing on mutations due to DNA damage;● if mutations do accumulate and the cell survives through many divisions (as is more likely if the p53 tumor-suppressor gene is defective or missing), cancer may ensue.
32 Multiple mutations underlie the development of cancer. ● more than 1 somatic mutation is generally needed to produce a full-fledged cancer cell;● this may help explain why the incidence of cancer increases greatly withage…● if cancer is the result ofan accumulation of mutations,& if mutations occur throughoutlife, then the longer we live, themore likely we are to developcancer.
35 Colorectal Cancer: ● about 135,000 new cases per year in the U.S. ● develops gradually – first sign usually a POLYP (small, benign growth in colon lining)● the tumor grows and eventually may become MALIGNANT● a malignant tumor will typically have cells with multiple oncogenes activated and multiple tumor-suppressor genes inactivated
38 Remember TELOMERES? ● in many malignant tumors, the gene for TELOMERASE is activated…● this enzyme prevents the erosion of the ends of chromosomes (the telomeres), thus removing a natural limit on the # of times the cells can divide…the tumor cells just keep on growing!
39 Breast Cancer:● in 5-10% of breast cancer cases, there is evidence of a strong inherited predisposition● in , researcher identified 2 genes involved these breast cancers: BRCA1 and BRCA2● both are considered tumor-suppressor genes (their wild-type alleles protect against breast cancer)● what the normal products of BRCA1 and BRCA2 actually do is still unknown…it seems as though they are both involved in the cell’s DNA damage repair pathway.
41 Viruses & Cancer:● viruses seem to play a role in about 15% of human cancer cases worldwideEXAMPLES:● retroviruses some forms of leukemia● hepatitis viruses some liver cancers● HPV cancer of the cervix