p57Kip2 knock-in mouse reveals CDK-independent contribution in the development of Beckwith–Wiedemann syndrome

Nicolas Duquesnes, Caroline Callot, Pauline Jeannot, Virginie Daburon, Keiichi I. Nakayama, Stephane Manenti, Alice Davy, Arnaud Besson

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)


CDKN1C encodes the cyclin–CDK inhibitor p57Kip2 (p57), a negative regulator of the cell cycle and putative tumour suppressor. Genetic and epigenetic alterations causing loss of p57 function are the most frequent cause of Beckwith–Wiedemann syndrome (BWS), a genetic disorder characterized by multiple developmental anomalies and increased susceptibility to tumour development during childhood. So far, BWS development has been attributed entirely to the deregulation of proliferation caused by loss of p57-mediated CDK inhibition. However, a fraction of BWS patients have point mutations in CDKN1C located outside of the CDK inhibitory region, suggesting the involvement of other parts of the protein in the disease. To test this possibility, we generated knock-in mice deficient for p57-mediated cyclin–CDK inhibition (p57CK ), the only clearly defined function of p57. Comparative analysis of p57CK and p57KO mice provided clear evidence for CDK-independent roles of p57 and revealed that BWS is not caused entirely by CDK deregulation, as several features of BWS are caused by the loss of CDK-independent roles of p57. Thus, while the genetic origin of BWS is well understood, our results underscore that the underlying molecular mechanisms remain largely unclear. To probe these mechanisms further, we determined the p57 interactome. Several partners identified are involved in genetic disorders with features resembling those caused by CDKN1C mutation, suggesting that they could be involved in BWS pathogenesis and revealing a possible connection between seemingly distinct syndromes.

Original languageEnglish
Pages (from-to)250-261
Number of pages12
JournalJournal of Pathology
Issue number3
Publication statusPublished - Jul 1 2016

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine


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