Multiple endocrine neoplasia type 1 (MEN1) is caused by germline mutations in the MEN1 gene encoding menin. Menin functions as a tumor suppressor. Which molecular function of menin explains why its loss promotes tumorigenesis in endocrine cells?
- A Menin is a scaffold protein in the Set1/MLL histone H3K4 methyltransferase complex; menin loss reduces H3K4me3 marks at tumor suppressor gene promoters (including CDKN1B/p27 and CDKN2C/p18), decreasing their expression and releasing the CDK4/CDK6-driven G1/S cell cycle brake in endocrine cells ✓
- B Menin is a membrane receptor for somatostatin that, when lost, removes growth inhibition in endocrine cells, causing autonomous proliferation
- C Menin directly binds p53 to stabilize it; menin loss causes p53 proteasomal degradation, abrogating the DNA damage response exclusively in islet cells
- D Menin is a GTPase-activating protein (GAP) that inactivates Ras; menin loss causes constitutive Ras-MAPK signalling driving endocrine cell proliferation
Explanation
Menin (encoded by MEN1 at chromosome 11q13) is a nuclear scaffold protein that forms an obligate component of the SET1/MLL1 and MLL2 histone H3 lysine 4 (H3K4) methyltransferase complexes — these complexes deposit the active transcription mark H3K4me3 at promoters of CDK inhibitor genes including CDKN1B (p27Kip1) and CDKN2C (p18INK4c). Loss of menin reduces H3K4me3 at these loci, epigenetically silencing CDK inhibitor expression. The resultant increase in CDK4/CDK6 activity hyperphosphorylates Rb, releasing E2F transcription factors to drive S-phase entry and cell proliferation — particularly in parathyroid, pituitary, and pancreatic islet cells that are exquisitely sensitive to p27 levels. This epigenetic mechanism explains the tissue-specific endocrine tumorigenesis in MEN1. Menin does not function as a somatostatin receptor, p53 stabilizer, or RasGAP.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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Written and medically reviewed by the StethoPrep medical team.