34 Cancer. Lecture Outline, 11/30/05. Cancer is caused by mutant genes. Changes in growth properties of cancer cells

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1 34 Cancer Lecture Outline, 11/30/05 Review the Cell cycle Cancer is a genetic disease Oncogenes and roto-oncogenes Normally romote cell growth. Become oncogenic after oint mutations, dulications, deletion of silencer, etc Tumor Suressor genes Normally inhibit cell growth. Allow cell growth when damaged or deleted. Mutator genes The multi-ste model of cancer Cancer is caused by mutant genes Changes in growth roerties of cancer cells Mutations in regulatory genes lead to uncontrolled cell growth Understanding gene regulation is one key to understanding cancer All cancers trace back to single cell Must accumulate multile mutations, all in the same cell lineage 1

2 The incidence of human cancers increases markedly with age It takes a long time for the causative mutations to accumulate in a cell The Human Cell Cycle ~ 1 hour ~ 4 hours ~ 10 hours ~ 9 hours Cell Cycle Regulators and Cancer Rb reresses E2F Free E2F is a transcrition activator Cyclin/Cdk inactivates Rb by hoshorylation 2

3 GTP Ras GTP Ras P53 is a transcrition factor that activates 21, an inhibitor of cyclin/cdk2 Signaling athways that regulate cell division (a) Cell cycle stimulating athway. This athway is triggered by 1 a growth factor that binds to 2 its recetor in the lasma membrane. The signal is relayed to 3 a G rotein called Ras. Like all G roteins, Ras is active when GTP is bound to it. Ras asses the signal to 4 a series of rotein kinases. The last kinase activates 5 a transcrition activator that turns on one or more genes for roteins that stimulate the cell cycle. If a mutation makes Ras or any other athway comonent abnormally active, excessive cell division and cancer may result. 1 Growth factor 3 G rotein Hyeractive Ras rotein MUTATION (roduct of oncogene) issues signals on its own 4 Protein kinases 2 Recetor (hoshorylation cascade) NUCLEUS 5 Transcrition factor (activator) DNA Gene exression Protein that stimulates the cell cycle (b) Cell cycle inhibiting athway. In this athway, 1 DNA damage is an intracellular signal that is assed via 2 rotein kinases and leads to activation of Activated 53 romotes transcrition of the gene for a rotein that inhibits the cell cycle. The resulting suression of cell division ensures that the damaged DNA is not relicated. Mutations causing deficiencies in any athway comonent can contribute to the develoment of cancer. UV light 2 Protein kinases 3 Active form of 53 1 DNA damage in genome DNA MUTATION Defective or missing transcrition factor, such as 53, cannot activate transcrition Protein that inhibits the cell cycle (c) Effects of mutations. Increased cell division, ossibly leading to cancer, can result if the cell cycle is overstimulated, as in (a), or not inhibited when it normally would be, as in (b). Protein overexressed EFFECTS OF MUTATIONS Protein absent Figure Cell cycle overstimulated Increased cell division Cell cycle not inhibited Stimulation versus inhibition of G1 rogression Stimulation of G1 rogression myc RB Inhibition S-hase entry mitogens ras cyclin D / cdk4 oncogenes RB P P P S-hase entry allowed PKB 27 DNA-damage Inhibition of G1 rogression RB Inhibition S-hase entry anti-mitogen (TGF-β) 15 cyclin D / cdk4 RB P P P S-hase entry allowed tumor suressor genes? 16 Oncogenes All are involved in ositive control of cell growth and division. About 100 different oncogenes have been identified Can be various kinds of roteins: Growth factors, regulatory genes involved in the control of cell multilication. Protein kinases, add hoshate grous to target roteins, imortant in signal transduction athways. Proto-oncogenes Normal form of the gene that is involved in ositive regulation of the cell cycle 3

4 Genetic changes that can turn roto-oncogenes into oncogenes Translocation uts abl under the control of a different romoter Proto-oncogene DNA Translocation or transosition: gene moved to new locus, under new controls Gene amlification Point mutation within a control element Point mutation within the gene New romoter Oncogene Oncogene Normal growth-stimulating rotein in excess Normal growth-stimulating rotein in excess Normal growth-stimulating Hyeractive or rotein in excess degradationresistant rotein Figure Translocation uts bcl near a new enhancer Ras Proto-oncogene Mutated in 30% of all cancers. A molecular switch in the signal transduction athway leading from growth factors to gene exression controlling cell roliferation: GF recetor Ras TF target genes growth. A single amino acid change in Ras rotein can cause constant stimulation of the athway, even in the absence of growth factors. 4

5 Recetor tyrosine kinases can activate ras ras is a monomeric G-rotein molecular switch You ve seen RAS before... PROBLEMS IN CANCER: - broken ras won t shut off Ras activation sets off a hoshorylation cascade MAPKK 1,000 MAPK 100,000 MAPKKK Mitogen Activated Protein Kinases MAPKs Controls: -Transcrition Factors -Translation Factors -Cell Division Oncogenes act cooeratively in tumor-induction - Broken recetor thinks ligand there even when it isn t -broken MAPK on all the time, even when not hoshorylated RESULT: continuous signal for cell to divide 5

6 Tumor Suressor Genes Normally inhibit cell growth Examle: retinoblastoma RB rotein normally blocks a transcrition factor, E2F 53 Gene Detects DNA damage The Last Gatekeeer Aotosis = controlled cell death Involved in 50% of cancers Often not malignant desite other cancer-causing mutations until 53 is inactivated by mutation. Two ossible resonses to DNA damage: 1) Acts as a Transcrition Factor to activate exression of 21, which inhibits CDK/G1 cyclin to halt the cell cycle; then activates DNA reair. 2) Triggers Aotosis (rogrammed cell death) if damage can t be reaied. executioner roteins (casases) break down the cell Reduced cell death can also lead to cancer 6

7 Aotosis athways htt:// Mutator genes Cancer is caused by mutations, so factors that increase mutation rate will increase cancer rate. What kinds of genes would increase mutation rate? Examle: BRCA1 and BRCA2 Many environmental factors (carcinogens) also cause DNA damage or mutations, that can lead to cancer A multiste model for the develoment of colorectal cancer Colon 1 Loss of tumor-suressor Colon wall gene APC (or other) Normal colon eithelial cells (1) The clonal origin of tumors: each individual cancer is a clone that arises from a single cell. The rogeny cells have growth advantage over the surrounding normal cells. (2) Cancer develoment is a multi-ste rocess. Multile mutations accumulated over eriods of many years ---- multi-hit model. Small benign growth (oly) 2 Activation of Ras oncogene 3 Loss of tumorsuressor gene DCC Larger benign growth (adenoma) 4 Loss of tumor-suressor gene 53 5 Additional mutations Malignant tumor (carcinoma) Figure