ONCOPATHOLOGY - 30 KEY SHORT ANSWER OmpathStudy

Comprehensive coverage: Molecular Basis of Cancer, Hallmarks of Cancer, and Carcinogenesis --- SECTION A: NORMAL CELL CYCLE & REGULATION (6 Questions) 1. Explain the role of the Cyclin D-CDK4 complex in regulating the G1/S checkpoint. Answer: Cyclin D synthesized in mid-G1 phase Binds to CDK4 forming Cyclin D-CDK4 complex Complex phosphorylates retinoblastoma (RB) protein Hypophosphorylated RB normally binds E2F transcription factor (inactive state) Phosphorylated RB releases E2F Free E2F activates transcription of genes for S phase (Cyclin E, DNA polymerases) Acts as molecular "on switch" for cell cycle progression 2. Describe the two main families of CDK inhibitors (CKIs) and their mechanisms. Answer: Cip/Kip family: Components: p21, p27, p57 Bind and inactivate Cyclin-CDK complexes p21 controlled by p53 tumor suppressor Important for DNA damage response INK4/ARF family: Encodes p16INK4a and p14ARF p16INK4a competes with Cyclin D for CDK4 binding Prevents RB phosphorylation → cell cycle arrest in late G1 Frequently mutated/hypermethylated in cancers Act as tumor suppressors 3. What happens at the G1/S and G2/M checkpoints? Answer: G1/S checkpoint: Checks for DNA damage before S phase S phase is "point of no return" If damage detected: repair mechanisms activated and cell cycle arrested If irreparable: apoptosis triggered Prevents replication of damaged DNA G2/M checkpoint: Monitors completion of DNA replication Ensures cell can safely initiate mitosis Critical after ionizing radiation exposure Defects lead to chromosomal abnormalities Prevents mitosis with incomplete/damaged DNA 4. Explain p53's role as "Guardian of the Genome." Answer: Central monitor of cellular stress Activated by: DNA damage, anoxia, inappropriate oncogene signaling Upon activation (by phosphorylation):Drives transcription of CDKN1A (p21) → blocks RB phosphorylation → G1/S arrest Allows time for DNA repair If repair fails: induces cellular senescence or apoptosis Mutated in ~70% of human tumors (biallelic loss) One defective allele in Li-Fraumeni Syndrome Can be inactivated by viral oncoproteins (HPV) 5. Describe how Cyclin B-CDK1 initiates mitosis. Answer: Cyclin A-CDK2 complex forms at G2/M transition Regulates events at mitotic prophase Cyclin B-CDK1 complex subsequently formed Activated by protein phosphatase Causes nuclear membrane breakdown Initiates mitosis proper Essential for M phase entry 6. What is the significance of E2F transcription factor in cell cycle progression? Answer: Bound and inactivated by hypophosphorylated RB in G1 Released when RB is phosphorylated by Cyclin D-CDK4 Activated E2F increases transcription of:Cyclin E (forms complex with CDK2) DNA polymerases Genes essential for S phase progression Drives DNA synthesis Also induces Cyclin A transcription for G2/M transition Master regulator of S phase entry --- SECTION B: ONCOGENES & SELF-SUFFICIENCY IN GROWTH (5 Questions) 7. Differentiate between proto-oncogenes and oncogenes. Answer: Proto-oncogenes: Normal physiologic regulators of cell proliferation and differentiation Required for normal growth and development Tightly regulated Examples: RAS, MYC, growth factor receptors Oncogenes: Mutated/altered versions of proto-oncogenes Promote autonomous cell growth even without normal mitogenic signals Oncoproteins lack important regulatory elements Constitutively active Contribute to cancer development 8. Explain how cancer cells achieve growth factor self-sufficiency. Answer: Normal cells require external growth factors for proliferation Cancer cells achieve autonomy through: Autocrine stimulation: Synthesize growth factors they can respond to (have receptors for same) Mutant receptors: Constitutively dimerized and activated without ligand binding Deliver continuous mitogenic signals Independence from external growth signals Examples: PDGF in gliomas, TGF-α in sarcomas 9. Describe the RAS oncogene and its role in cancer. Answer: RAS = signal-transducing protein Located under cell membrane Normal function: receives signals from growth factor receptors, transmits to nucleus In cancers:Point mutations prevent GTPase activity RAS locked in active GTP-bound state Continuous proliferative signaling No external growth factor needed Mutations in RAS family (HRAS, KRAS, NRAS) found in ~30% human cancers Especially common in pancreatic, colon, lung cancers 10. How does the BCR-ABL fusion protein cause cancer? Answer: Results from t(9;22) Philadelphia chromosome translocation Occurs in Chronic Myeloid Leukemia (CML) and some ALL c-ABL gene (chromosome 9) fused to BCR gene (chromosome 22) BCR-ABL fusion protein produced Loss of regulatory region controlling tyrosine kinase activity Constitutively active tyrosine kinase Continuous proliferative signaling independent of growth factors Targeted by imatinib (Gleevec) - tyrosine kinase inhibitor 11. Explain the role of MYC oncogene in human cancers. Answer: Most commonly involved oncogene in human cancers Nuclear transcription fact