Mutations in the PCNA-binding site of CDKN1C inhibit cell proliferation by impairing the entry into S phase.
Mutations in the PCNA-binding site of CDKN1C inhibit cell proliferation by impairing the entry into S phase.
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DOI：
10.1186/s13008-015-0008-8
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发表时间：
2015
期刊：
影响因子：
2.3
通讯作者：
Vilain E
中科院分区：
文献类型：
--
作者：
Borges KS;Arboleda VA;Vilain E
CDKN 1C（也称为P57 kip 2）是一种细胞周期蛋白依赖性激酶抑制剂，通过G1期细胞周期停滞作为细胞增殖的负调节剂发挥作用。最近，我们的研究小组描述了CDKN 1C的PCNA结合位点的功能获得性突变，其导致称为IMAGe综合征（宫内生长受限，干骺端发育不良，肾上腺发育不全和生殖器异常）的生长不足综合征，具有危及生命的后果。在5-10%的Beckwith-Wiedemann综合征（BWS）患者中发现了CDKN 1C的功能缺失突变，BWS是一种过度生长疾病，其特征与IMAGe综合征相反。在这里，我们研究IMAGe相关突变对蛋白质稳定性，细胞周期进程和细胞增殖的影响。CDKN 1C的PCNA结合位点的突变显著增加CDKN 1C蛋白的稳定性，并阻止细胞周期进展到S期。野生型或BWS突变型CDKN 1C的过表达抑制细胞增殖。然而，IMAGe突变的CDKN 1C蛋白比野生型或BWS蛋白显著地降低细胞生长。这些发现为IMAGe综合征潜在的分子事件带来了新的见解。
CDKN1C (also known as P57kip2) 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.
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CDKN1C的蛋白质稳定性提高会导致图像综合征患者的功能型表型。
影响因子：
3.7
作者：
Hamajima N;Johmura Y;Suzuki S;Nakanishi M;Saitoh S
通讯作者：
Saitoh S
影响因子：
4.3
作者：
Zhao, Ruiying;Yang, Heng-Yin;Lee, Mong-Hong
通讯作者：
Lee, Mong-Hong
影响因子：
30.8
作者：
Arboleda VA;Lee H;Parnaik R;Fleming A;Banerjee A;Ferraz-de-Souza B;Délot EC;Rodriguez-Fernandez IA;Braslavsky D;Bergadá I;Dell'Angelica EC;Nelson SF;Martinez-Agosto JA;Achermann JC;Vilain E
通讯作者：
Vilain E
影响因子：
2
作者：
Romanelli, Valeria;Belinchon, Alberta;Lapunzina, Pablo
通讯作者：
Lapunzina, Pablo
影响因子：
64.5
作者：
GIRARD, F;STRAUSFELD, U;LAMB, NJC
通讯作者：
LAMB, NJC