CDKN1C

CDKN1C encodes p57Kip2, a cyclin-dependent kinase inhibitor of the CIP/Kip family that functions as a tumor suppressor by binding to and inhibiting cyclin/CDK complexes, particularly cyclin E/CDK2, cyclin A/CDK2, and cyclin D/CDK4. The N-terminal kinase inhibitory domain (KID) blocks ATP binding to CDKs through molecular mimicry. The protein contains a unique PAPA (proline-alanine repeat) domain, a QT box mediating additional protein interactions, bipartite nuclear localization signals (NLS), and a C-terminal PCNA-binding domain. p57Kip2 dynamically shuttles between cytoplasm (during proliferation) and nucleus (during differentiation) to regulate cell cycle exit. The gene is imprinted and expressed exclusively from the maternal allele; loss-of-function mutations cause Beckwith-Wiedemann syndrome and IMAGe syndrome. Beyond CDK inhibition, p57Kip2 inhibits JNK/SAPK signaling independently and regulates E2F1-mediated transcription by inhibiting RNA polymerase II CTD phosphorylation.

Disorders

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