title: Mutations in the PCNA-binding site of CDKN1C inhibit cell proliferation by impairing the entry into S phase.
abstract: CDKN1C (also known as P57 (kip2) ) is a cyclin-dependent kinase inhibitor that functions as a negative regulator of cell proliferation through G1 phase cell cycle arrest. Recently, our group described gain-of-function mutations in the PCNA-binding site of CDKN1C that result in an undergrowth syndrome called IMAGe Syndrome (Intrauterine Growth Restriction, Metaphyseal dysplasia, Adrenal hypoplasia, and Genital anomalies), with life-threatening consequences. Loss-of-function mutations in CDKN1C have been identified in 5-10% of individuals with Beckwith-Wiedemann syndrome (BWS), an overgrowth disorder with features that are the opposite of IMAGe syndrome. Here, we investigate the effects of IMAGe-associated mutations on protein stability, cell cycle progression and cell proliferation. Mutations in the PCNA-binding site of CDKN1C significantly increase CDKN1C protein stability and prevent cell cycle progression into the S phase. Overexpression of either wild-type or BWS-mutant CDKN1C inhibited cell proliferation. However, the IMAGe-mutant CDKN1C protein decreased cell growth significantly more than both the wild-type or BWS protein. These findings bring new insights into the molecular events underlying IMAGe syndrome.
authors: Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, 695 Charles E. Young Drive, Los Angeles, CA 90095 USA ; Department of Genetics, Ribeirão Preto Medical School, University of São, Ribeirão Preto, Av. Bandeirantes 3900, CEP 14049-900 Ribeirão Preto, SP Brazil.
authors: Kleiton S
authors: KS
authors: Borges
authors: Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, 695 Charles E. Young Drive, Los Angeles, CA 90095 USA ; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, USA.
authors: Valerie A
authors: VA
authors: Arboleda
authors: Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, 695 Charles E. Young Drive, Los Angeles, CA 90095 USA ; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, USA ; Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, USA.
authors: Eric
authors: E
authors: Vilain
keywords: Beckwith Wiedemann syndrome; CDK-inhibitor; Cell cycle; Cyclin; IMAGe syndrome; Intrauterine growth restriction