p53

**Function / Pathophysiology** - Nuclear phosphoprotein and transcription factor encoded by TP53 (chromosome 17p13). - Normally kept at low levels: MDM2 (an E3 ubiquitin ligase) binds p53 and targets it for proteasomal degradation. - DNA damage activates ATM/ATR and Chk1/Chk2, which phosphorylate p53. This blocks MDM2 binding, so p53 is stabilized and accumulates. - Active p53 transcribes: - **p21 (CDKN1A):** inhibits cyclin-CDK complexes, so Rb stays hypophosphorylated and bound to E2F. This causes G1 arrest, giving time for DNA repair. - **GADD45:** promotes DNA repair. - **BAX, PUMA, NOXA:** promote apoptosis if damage is irreparable. - Net effect: prevents replication of damaged DNA. Loss of p53 allows cells with DNA damage to proliferate, accumulate mutations, and become malignant.

**Genetics** - Follows the Knudson two-hit hypothesis. Both alleles must be inactivated (loss of function). - Mutant p53 often acts as a dominant negative, because mutant subunits in the tetramer inactivate the wild-type protein. - Somatic TP53 mutations occur in more than 50% of human cancers (e.g., colon, lung, breast, ovarian, and many others).

**Li-Fraumeni syndrome** - Autosomal dominant germline TP53 mutation. - Mnemonic **SBLAST**: Sarcoma, Breast, Leukemia, Adrenal cortical carcinoma, Brain tumors (e.g., glioma), and other Sarcomas/Tumors. - Early-onset, multiple primary cancers. Often follows the "rule of 45" (e.g., sarcoma <45 years, plus a first-degree relative with cancer <45 years).

**Viral oncoproteins that inactivate p53 (and Rb)** - HPV E6 degrades p53 (via E6-AP ubiquitin ligase). HPV E7 inhibits Rb. This is the mechanism in cervical cancer. - SV40 large T antigen and adenovirus E1B also inactivate p53.

**Other clinical associations** - MDM2 amplification (e.g., liposarcoma) causes functional p53 loss. - p53 is often overexpressed on immunohistochemistry in tumors because mutant protein has a longer half-life and accumulates. Wild-type p53 has a short half-life. - Aflatoxin B1 (Aspergillus) causes a G→T transversion at codon 249 of p53, which contributes to hepatocellular carcinoma. - Ataxia-telangiectasia (ATM mutation) impairs p53 activation. - Therapies: many chemotherapy and radiation agents act by inducing DNA damage and p53-mediated apoptosis, so p53-mutant tumors are often more resistant.

**Board pearls** - Think "p53 = guardian of the genome": it stops the cell cycle at G1/S and triggers apoptosis. - Rb = "gatekeeper" of G1/S. p53 acts upstream via p21. - Tumor suppressors (p53, Rb, APC, BRCA1/2, NF1, WT1, VHL) require loss of both alleles. Oncogenes need only a gain-of-function change in one allele.