Pocket Oncology (Pocket Notebook Series), 1st Ed.

APOPTOSIS & TP53

Alexander Drilon

Transcriptional Regulation

• Gene expression is modulated by transcription factors that bind to gene promoter regions

• Steroid hormones bind to specific steroid hormone receptors (eg, ER & PR in breast cancer, RAR in acute promyelocytic leukemia (APL)) that translocate to nucleus → bind to response elements that ↑ target gene expression

Figure 4-7

Apoptosis

• Physiologic process of cell death orchestrated by several biochemical processes

• Apoptosis is triggered by two mechanisms:

Extrinsic pathway: Similar to growth signaling pathways, an external signal or ligand (tumor necrosis factor or Fas ligand) binds to transmembrane receptors (TNFR & Fas, respectively) → death domains (TRADD & FADD) exposed → procaspases activated to caspases → results in proteolysis of target proteins in cell

Intrinsic pathway: Cell stress or DNA damage such as in the face of radiation or chemotherapy → mitochondrial membrane change releasing cytochrome C → forms apoptosome w/APAF-1 & procaspase → caspases activated (can be inhibited by IAPs whose expression is mediated by NF-kB) (Nat Rev Cancer 2009;9:501)

BCL-2 family: Mediate mitochondrial permeability & cytochrome C release

• In contrast, senescence is a process by w/c cells stop dividing after a finite number of replicative cycles; telomeres (repetitive DNA sequences at chromosome ends) shorten w/each replication limiting this number of cycles → several CAs upregulate telomerase w/c maintains telomere length via hTERT (reverse transcriptase) (Cell 2012;22:211)

TP53: Genome Guardian

• Integrates many alarm signals → depending on severity of signals wild-type TP53 can arrest cell cycle leading to senescence, promote DNA repair, initiate apoptosis, & block angiogenesis (Nat Cell Biol2013;15:2)

• ↓ TP53 levels: MDM2 ubiquitinates TP53 tagging it for degradation

• ↑ TP53 levels: (1) ARF sequesters MDM2, (2) in the face of DNA damage CHK2, ATM, ATR phosphorylate TP53 thus activating it, (3) under cellular stress, ATR & casein kinase similarly phosphorylate TP53

• Li–Fraumeni syndrome: Germline TP53 Mt, leads to ↑ predisposition to sarcomas, breast CA, leukemias, brain tumors, adrenocortical carcinomas