p57^Kip2knock-in mouse reveals CDK-independent contribution in the development of Beckwith-Wiedemann syndrome

Abstract

CDKN1C encodes the cyclin-CDK inhibitor p57(Kip2) (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 (p57(CK) (-) ), the only clearly defined function of p57. Comparative analysis of p57(CK) (-) and p57(KO) 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. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chromosomal rearrangements in the 11p15 imprinted region: 17 new 11p15.5 duplications with associated phenotypes and putative functional consequences

“…Expression of the paternal allele of this gene is required for silencing CDKN1C expression on the same allele. As a cell cycle inhibitor, paternally imprinted/maternally expressed CDKN1C tends to restrain fetal growth 39. Thus, duplications of the whole centromeric domain lead to increased expression of CDKN1C and therefore growth restriction when maternally transmitted, whereas it has no impact on growth when it occurs on the paternal allele (patients 3–6 and 14–17 and references27 30).…”

The CDK inhibitor p57Kip2 enhances the activity of the transcriptional coactivator FHL2

“…Interestingly, alterations of the p57 coding gene CDKN1C have been frequently observed in BWS patients and genetic and epigenetic alterations impairing p57 expression or function are the most frequent cause of BWS [5][6][7] . However, some BWS patients carry mutations outside the cyclin/CDK binding domain and mouse knock-in studies revealed a CDK-independent contribution of p57 in BWS 8 . Therefore, not all of the observed phenotypes can be attributed to the ability of p57 to bind and to inhibit cyclin/CDK complexes 8,9 .…”

“…However, some BWS patients carry mutations outside the cyclin/CDK binding domain and mouse knock-in studies revealed a CDK-independent contribution of p57 in BWS 8 . Therefore, not all of the observed phenotypes can be attributed to the ability of p57 to bind and to inhibit cyclin/CDK complexes 8,9 . Some phenotypes of p57-deficient mice were even enhanced when a cyclin/CDK binding deficient mutant (p57 CK− ) was expressed in mice, indicating additional dominant effects of the p57 CK− mutant by so far unknown mechanisms 8 .…”

Management of adrenal masses in patients with Beckwith–Wiedemann syndrome

“…Alterations in CDKN1C expression have also been tied to changes in adrenal growth and development. In a Cdkn1c knockdown mouse model, adrenal cell hyperplasia was noted, most notably in the adrenal cortex . Alternatively, patients with gain of function CDKN1C mutations are phenotypically growth restricted, and in particular have adrenal hypoplasia …”

“…In a Cdkn1c knockdown mouse model, adrenal cell hyperplasia was noted, most notably in the adrenal cortex. 44 hypertrophy, as well as predisposition to adrenocortical malignancy.…”