Mutations in the PCNA-binding site of CDKN1C inhibit cell proliferation by impairing the entry into S phase

Author(s)

Borges, Kleiton S. ^{[1, 2]} ; Arboleda, Valerie A. ^{[1, 3]} ; Vilain, Eric ^{[1, 4, 5]}

Affiliation

^[1] Univ Calif Los Angeles, Dept Human Genet, David Geffen Sch Med UCLA, Los Angeles, CA 90095 - USA

^[2] Univ Sao, Ribeirao Preto Med Sch, Dept Genet, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Univ Calif Los Angeles, Dept Pathol & Lab Med, David Geffen Sch Med, Los Angeles, CA 90095 - USA

^[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 - USA

^[5] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 - USA

• Document type: Journal article
• Source: CELL DIVISION; v. 10, MAR 28 2015.
• Web of Science Citations: 1

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. (AU)

• FAPESP's process: 12/09391-0 - Molecular investigation of the role of CDKN1C (p57KIP2) and its mutations in adrenal development and tumor
• Grantee: Kleiton Silva Borges
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate