Differential post-transcriptional regulation of two Ink4 proteins, p18 Ink4c and p19 Ink4d.
Differential post-transcriptional regulation of two Ink4 proteins, p18 Ink4c and p19 Ink4d.
复制标题
DOI：
10.4161/cc.7.23.7187
复制
发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Roussel MF
中科院分区：
文献类型：
--
作者：
Forget A;Ayrault O;den Besten W;Kuo ML;Sherr CJ;Roussel MF
Ink 4家族的细胞周期蛋白（-D-）依赖性激酶（Cdk）抑制剂特异性结合Cdk 4和Cdk 6，但不结合其它Cdk。Ink 4c和Ink 4d mRNA在细胞分裂周期的G2/M期期间最大限度地和周期性地表达，但其编码的蛋白质的丰度通过不同的机制进行调节。这两种蛋白质都经历了多泛素化，但p18 Ink 4c的半衰期（约10小时）比p19 Ink 4d的半衰期（约2.5小时）长得多。赖氨酸46和112是p18 Ink 4c中泛素结合的优选位点，尽管用精氨酸取代这些和其他赖氨酸残基，特别是组合，引发蛋白质错误折叠并加速p18 Ink 4c降解。当与催化活性或无活性的Cdk 4或Cdk 6连接时，p18 Ink 4c的多聚泛素化被抑制，并且蛋白质进一步稳定。相反，在与p18 Ink 4c竞争与Cdks结合时，细胞周期蛋白D1加速了p18 Ink 4c的周转。与此相反，p19 Ink 4d的多聚泛素化是由其与Cdks的结合诱导的，而细胞周期蛋白D1的过表达则延缓了p19 Ink 4d的降解。虽然人们普遍认为p18 Ink 4c和p19 Ink 4d是生物化学上相似的Cdk抑制剂，但它们在稳定性和周转率方面的主要差异可能是理解它们独特生物学功能的关键。
Cyclin(-D-)-dependent kinase (Cdk) inhibitors of the Ink4 family specifically bind to Cdk4 and Cdk6, but not to other Cdks. Ink4c and Ink4d mRNAs are maximally and periodically expressed during the G2/M phase of the cell division cycle, but the abundance of their encoded proteins is regulated through distinct mechanisms. Both proteins undergo polyubiquitination, but the half life of p18Ink4c (~10 hours) is much longer than that of p19Ink4d (~2.5 hours). Lysines 46 and 112 are preferred sites of ubiquitin conjugation in p18Ink4c, although substitution of these and other lysine residues with arginine, particularly in combination, triggers protein misfolding and accelerates p18Ink4c degradation. When tethered to either catalytically active or inactive Cdk4 or Cdk6, polyubiquitination of p18Ink4c is inhibited, and the protein is further stabilized. Conversely, in competing with p18Ink4c for binding to Cdks, cyclin D1 accelerates p18Ink4c turnover. In direct contrast, polyubiquitination of p19Ink4d is induced by its association with Cdks, whereas cyclin D1 overexpression retards p19Ink4d degradation. Although it has been generally assumed that p18Ink4c and p19Ink4d are biochemically similar Cdk inhibitors, the major differences in their stability and turnover are likely key to understanding their distinct biological functions.
登录
查看更多内容
影响因子：
4.4
作者：
Barton, LF;Runnels, HA;Monaco, JJ
通讯作者：
Monaco, JJ
影响因子：
4.8
作者：
Ben-Saadon, R;Fajerman, I;Ciechanover, A
通讯作者：
Ciechanover, A
影响因子：
64.8
作者：
Molofsky, Anna V.;Slutsky, Shalom G.;Morrison, Sean J.
通讯作者：
Morrison, Sean J.
影响因子：
64.8
作者：
Lowe, SW;Cepero, E;Evan, G
通讯作者：
Evan, G
影响因子：
64.8
作者：
Janzen, Viktor;Forkert, Randolf;Scadden, David T.
通讯作者：
Scadden, David T.