The RAS proto-oncogene product is a GTPase involved in the MAPK proliferative signalling cascade. Oncogenic point mutations at codons 12 or 13 of KRAS lead to persistent tumour cell proliferation because:
- A Mutant RAS cannot hydrolyse GTP to GDP, locking RAS in a constitutively active (GTP-bound) state ✓
- B Mutant RAS continuously activates adenylyl cyclase, maximising cAMP-mediated proliferation
- C Mutant RAS overactivates RAS-GAP, accelerating growth factor receptor signalling
- D Mutant RAS gains ability to bind GTP with greater affinity, increasing signal amplitude
Correct answer: A. Mutant RAS cannot hydrolyse GTP to GDP, locking RAS in a constitutively active (GTP-bound) state
Explanation
Normal RAS cycles between inactive GDP-bound and active GTP-bound states; the intrinsic GTPase activity (accelerated by GTPase-activating proteins, GAPs) terminates signalling. Glycine12 or glycine13 substitutions in oncogenic KRAS sterically prevent GAP-catalysed GTP hydrolysis, locking RAS-GTP on and continuously activating downstream RAF-MEK-ERK (MAPK) and PI3K-Akt pathways — key drivers of KRAS-mutant lung, pancreatic, and colorectal cancers.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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