Molecular Biology of Cancer Flashcards
Cancer
Disease characterized by loss of regulation of the cell cycle, normal checkpoints are bypassed, allowing defective DNA replication and cell division, greater frequency of aneuploidy
Causes of cancer
Mutations lead to uncontrolled proliferation of cells, occur as a result of ionizing and UV radiation, chemicals, spontaneous errors during replication
Normal detection of mutations
Cell has mechanisms for detecting mutations and halting genetic processes until corrections are made, if the mutation is severe, the cell undergoes apoptosis
Uncontrollable growth
Mutated cells proliferate and develop further mutations, tumor becomes most dangerous when it gains the ability to invade surrounding tissues and proliferate in distant sites (metastasis)
Defects in DNA repair
BRCA-1,2, causes breast, ovarian, and prostate cancer, repair by homologous recombination
Differences between normal cells and malignant cells
Infinite proliferative capacity, anchorage independent, resistant to growth inhibition, resistant to apoptosis, show signs of de-differentiation, can be metastatic
Oncogenes
Result from gain-of-function mutations of growth-promoting genes, corresponding normal gene is a proto-oncogene
Tumor suppressor genes
Normal genes that encode growth-inhibiting products that become inactivated in cancer cells (loss-of-function), inhibition of growth-inhibiting activities results in unregulated cell growth
Varmus and Bishop
Hypothesized that cancer is caused by mutations in cellular genes (not viruses), many v-onc have been isolated from retroviruses, cellular proto-oncogenes (c-onc) have been found
Classes of cellular proto-oncogenes (c-onc)
Cellular growth factors, hormone and growth factor receptors, signal transduction proteins, GTP-binding proteins, nonreceptor protein kinases, transcription factors
Cell cycle
Activated by growth factors, hormone messengers, work through cyclins and cyclin-dependent kinases (CDKs), regulated by phosphorylation and cyclin-dependent kinase inhibitors (CKIs)
Conversion of proto-oncogene to oncogenes
Radiation or chemical mutagen, gene rearrangement- places proto-oncogene under control of strong transcriptional activator and fuses with with another protein, gene amplification
Mitogen activated protein kinase pathway
MAP kinase pathway activates transcription of myc and fos, phosphorylates AP-1 (fos and jun)
Ras
Monomeric G-protein in the cascade mediating cell growth/mitosis control by growth factors
Ras activation
Growth factors bind to receptors, relay signal to intracellular GTPases (like Ras), Ras becomes activated by binding GTP
Effect of stimulation of Ras
Stimulates phosphorylation cascade (MAP kinase cascade) that leads to activation of nuclear proteins that activate transcription, cell cycle is activated
Ras activation of the cell cycle
Mutations cause Ras to remain in active (GTP-bound) conformation leading to oncogenesis, Ras mutations are found in 20-25% of human tumors and up to 90% of specific tumor types
Neurofibromin (NF-1)
NF-1 activates Ras GTPase, NF-1 is a tumor suppressor, mutations in NF-1 cause neurofibromatosis
Retinoblastoma
Tumors from embryonic neural retina, occurs in young children, led to isolation of retinoblastoma suppressor gene Rb-1
Retinoblastoma protein (Rb)
Tumor suppressor product of the retinoblastoma gene, protein that functions as a negative regulator of cell cycle, arrests cells in G1 phase, halts cell proliferation
Action of retinoblastoma protein (Rb)
Binds to transcription factors (E2F1), unphosphorylated during the G0 and G1 phases, multiply phosphorylated during S and G2/M phases
Rb and the cell cycle
Binds and inactivates E2F (initiates the G1/S cell cycle transition), Rb controls a crucial cell cycle checkpoint- G1/S
Key regulators of cell cycle
p16/INK4, cyclin D, CDK4, Rb, at least one is dysregulated in vast majority of human cancers
p53
Transcription factor regulating cell cycle, DNA repair, and programmed cell death, senses DNA damage or hypoxia
Actions of p53
Upon sensing DNA damage it: halts cell cycle so new DNA synthesis will not replicate damaged DNA, up-regulates genes involved in DNA repair, and stimulates apoptosis if damage is severe
p53 mutation
Most frequent mutation leading to cancer
Li Fraumeni syndrome
Genetic defect in p53 leads to a high frequency of cancer in affected individuals
p27
Inhibits cyclin and Cdk, blocking entry into S phase, used for breast cancer prognosis, reduced levels of p27 predict poor outcome for breast cancer
Role of cell adhesion
Cadherins bind cells together, anchored by catenins and actin, loss of E-cadherin allows detachment and metastasis, catenins also function as transcription factors
CDH1
Mutation in E-cadherin- diffuse gastric cancer
APC
Adenomatous polyposis coli, inhibits beta-catenin, mutations cause sporadic colon cancer, inherited mutations cause familial adenomatous polyposis (FAP)
Apoptosis
Programmed cell death, cells are no longer needed, executed by caspases
Activation of caspases
Activated by ligands, such as tumor necrosis factor (TNF) binding the death receptor or by cytochrome c from mitochondria
Death receptors
Fas/CD95, TNF-receptor 1 (TNF-R1), death receptor 3 (DR3)
Death receptor pathway
Activated receptor binds two inhibitor caspases (8, 10) which activate each other, they activate execution caspases (3, 6, 7), caspase 3 activates a Bcl-2 family member Bid which affects mitochondrial integrity
Activation of caspases
Synthesized as inactive precursors called procaspases, once activated they cleave other procaspases to activate them, resulting in amplifying proteolytic cascade
Activation of apoptotic procaspases
Activated by an apoptosome composed of cytochrome c and Apaf-1 (pro-apoptotic protease activating factor-1)
Bcl-2 family proteins
Signal integration, 30 homologous proteins with BH domains, 4 BH domains = anti-apoptosis, 3 BH = form channels, 1 BH = pro-apoptosis
Philadelphia chromosome
Results from translocation between the long arms of chromosome 9 and 22, creates Bcr-Abl fusion protein, Abl is tyrosine kinase (proto-oncogene) and part of signaling cascade, when fused with Bcr it is always active, can lead to chronic myelogenous leukemia (CML)
Burkitt’s lymphoma
Caused by oncogenic transformation due to translocation, causes c-myc gene to be controlled by the promoter for immunoglobulin heavy chain gene, c-myc is transcription factor, synthesized at high levels induces proliferation of white blood cells
N-myc amplification
Amplified in neuroblastoma, occurs as double minutes, chromosomally integrated homogenous staining region (HSR)
Nonsurgical cancer treatment- target DNA replication
Anti-folates, base analogues, alkylating agents, ionizing radiation
Anti-folates
Target thymidylate synthase, purine synthesis, ex- methotrexate)
Base analogues
Target thymidylate synthase, ex- 5-Fluorouracil
Alkylating agents
Damage DNA, triggers apoptosis, ex- cyclophosphamide, cisplatin, cancer cells with inactive p53 proteins can avoid apoptosis
Ionizing radiation
Damages DNA, triggers apoptosis, cancer cells with inactive p53 proteins can avoid apoptosis
Nonsurgical cancer treatment- interfere with mitotic apparatus
Microtubule depolymerizing drugs (vinblastine), microtubule polymerizing drugs (taxol), inhibit microtubule function during mitosos of the cell cycle, causing mitotic arrest
Nonsurgical cancer treatment- choke off blood supply
Drugs that block angiogensis, drugs blocking VEGF (Avastin)
Nonsurgical cancer treatment- target oncogenic proteins with inhibitors
Monoclonal antibodies (herceptin- blocks Her2 receptor, Her2 overexpressed in breast tumors), active site inhibitors (Gleevec- binds active site of Bcr-abl tyrosine kinase and inactivates it)
Important tumor suppressor genes
Normally control cell cycle and proliferation, Rb, CDK inhibitors (p21, p27, INK4/p16)
Important oncogenes
Enhance cell proliferation when activated, Ras, myc, abl
Important DNA repair genes
Help maintain integrity of genome, BRCA1, BRCA2, mismatch repair genes
