P57(KIP2), A STRUCTURALLY DISTINCT MEMBER OF THE P21(CIP1) CDK INHIBITOR FAMILY, IS A CANDIDATE TUMOR-SUPPRESSOR GENE
P57(KIP2), A STRUCTURALLY DISTINCT MEMBER OF THE P21(CIP1) CDK INHIBITOR FAMILY, IS A CANDIDATE TUMOR-SUPPRESSOR GENE
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DOI：
10.1101/gad.9.6.650
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发表时间：
1995-03-15
影响因子：
10.5
通讯作者：
ELLEDGE, SJ
中科院分区：
文献类型：
--
作者：
MATSUOKA, S;EDWARDS, MC;ELLEDGE, SJ
细胞周期蛋白依赖性激酶（Cdks）是细胞增殖的正调节因子，而Cdk抑制剂（CKIs）抑制增殖。我们描述了一种新的CKI，p57（KIP 2），它与p21（CIP 1）和p27（KIP 1）相关。p57（KIP 2）是一种强有力的、紧密结合的G（1）cyclin/Cdk复合物抑制剂，其结合依赖于cyclin。与CIP 1不同，KIP 2不受p53调控。p57（KIP 2）的过表达使细胞停滞在G（1）。p57（KIP 2）蛋白具有复杂的结构。小鼠p57（KIP 2）由四个结构不同的结构域组成：氨基端Cdk抑制结构域、富含脯氨酸结构域、酸性重复区和与p27（KIP 1）保守的羧基端结构域。人p57（KIP 2）似乎具有保守的氨基和羧基末端结构域，但用含有脯氨酸-丙氨酸重复序列的序列取代了内部区域。小鼠胚胎发生过程中的原位杂交显示，KIP 2 mRNA在发育过程中显示出惊人的表达模式，在骨骼肌、脑、心脏、肺和眼睛中显示出高水平的表达。大多数表达KIP 2的细胞是终末分化的，这表明p57（KIP 2）参与了发育和分化过程中退出细胞周期的决定。人KIP 2位于11p15.5，这是一个与散发性癌症和家族性癌症综合征Beckwith-Wiedemann综合征有关的区域，标志着它是一个候选的肿瘤抑制因子。p21（CIP 1）抑制剂家族的新成员的发现，具有新的结构特征和表达模式，表明这些蛋白质在细胞周期控制和发育中的复杂作用。
Cydin-dependent kinases (Cdks) are positive regulators of cell proliferation, whereas Cdk inhibitors (CKIs) inhibit proliferation. We describe a new CKI, p57(KIP2), which is related to p21(CIP1) and p27(KIP1). p57(KIP2) is a potent, tight-binding inhibitor of several G(1) cyclin/Cdk complexes, and its binding is cyclin dependent. Unlike CIP1, KIP2 is not regulated by p53. Overexpression of p57(KIP2) arrests cells in G(1). p57(KIP2) proteins have a complex structure. Mouse p57(KIP2) consists Of four structurally distinct domains: an amino-terminal Cdk inhibitory domain, a proline-rich domain, an acidic-repeat region, and a carboxy-terminal domain conserved with p27(KIP1). Human p57(KIP2) appears to have conserved the amino- and carboxy-terminal domains but has replaced the internal regions with sequences containing proline-alanine repeats. In situ hybridization during mouse embryogenesis revealed that KIP2 mRNA displays a striking pattern of expression during development, showing high level expression in skeletal muscle, brain, heart, lungs, and eye. Most of the KIP2-expressing cells are terminally differentiated, suggesting that p57(KIP2) is involved in decisions to exit the cell cycle during development and differentiation. Human KIP2 is located at 11p15.5, a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome, a familial cancer syndrome, marking it as a candidate tumor suppressor. The discovery of a new member of the p21(CIP1) inhibitor family with novel structural features and expression patterns suggests a complex role for these proteins in cell cycle control and development.