Biologic and biochemical analyses of p16(INK4a) mutations from primary tumors.
Biologic and biochemical analyses of p16(INK4a) mutations from primary tumors.
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原发性肿瘤 p16(INK4a) 突变的生物学和生化分析。
DOI：
10.1093/jnci/91.18.1569
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Liu,ET
中科院分区：
文献类型：
--
作者：
Yarbrough,WG;Buckmire,RA;Bessho,M;Liu,ET
背景：肿瘤抑制基因 p16INK4a（也称为 p16、CDKN2、MTS1 和 INK4a）的点突变存在于许多肿瘤类型中。由于这些天然存在的突变体产物的功能尚未得到充分探索，我们研究了多种天然存在的 p16 突变蛋白的功能活性。方法：对错义突变产生的 16 种癌症相关 p16 突变蛋白进行了表征，了解它们结合和抑制细胞周期蛋白依赖性激酶（CDK4 和 CDK6）以及诱导细胞周期停滞在 G1 期的能力。结果/结论：在分析的 16 个突变体中，9 个具有可检测到的功能缺陷。三种突变体（D84V、D84G 和 R87P）在 CDK 结合、激酶抑制和细胞周期停滞方面存在缺陷。相应的突变位于高度保守区域的第三个锚蛋白重复区域，据信形成CDK结合裂口。三种突变体（P48L、D74N 和 R87L）在激酶抑制和细胞周期停滞方面存在缺陷。在具有正常CDK结合和抑制活性的10个突变体中，三个突变体（N71S、R80L和H83Y）仅在诱导细胞周期停滞的能力方面存在缺陷。 因此，保留CDK4和CDK6结合的p16突变蛋白可能具有更微妙的功能缺陷。导致功能障碍的所有九个突变都映射到 p16 蛋白的中心部分。锚蛋白重复序列 II 和 III 似乎对 p16 功能更为关键，而锚蛋白重复序列 I 和 IV 的突变不太可能破坏 p16 功能。
BACKGROUND: Point mutations in the tumor suppressor gene p16INK4a(also known as p16, CDKN2, MTS1, and INK4a) are found in many tumor types. Because the function of the products of these naturally occurring mutants has not been fully explored, we investigated the functional activities of a wide range of naturally occurring p16 mutant proteins. METHODS: Sixteen cancer-associated p16 mutant proteins, resulting from missense mutations, were characterized for their ability to bind and inhibit the cyclin-dependent kinases (CDK4 and CDK6) and to induce cell cycle arrest in G1phase. RESULTS/CONCLUSIONS: Among 16 mutants analyzed, nine had detectable functional defects. Three mutants (D84V, D84G, and R87P) had defects in CDK binding, kinase inhibition, and cell cycle arrest. The corresponding mutations are located in the third ankyrin repeat in a highly conserved region believed to form the CDK binding cleft. Three mutants (P48L, D74N, and R87L) had defects in kinase inhibition and cell cycle arrest. Among the 10 mutants with normal CDK binding and inhibitory activity, three mutants (N71S, R80L, and H83Y) had defects only in their ability to induce cell cycle arrest. Thus, p16 mutant proteins that retain CDK4 and CDK6 binding may have more subtle functional defects. All nine mutations leading to functional impairments mapped to the central portion of the p16 protein. Ankyrin repeats II and III appear more critical to p16 function, and mutations in ankyrin repeats I and IV are less likely to disrupt p16 function.
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影响因子：
11.2
作者：
S. Y. Zhang;Andres J Klein-Szanto;E. Sauter;M. Shafarenko;S. Mitsunaga;T. Nobori;D. Carson;J. Ridge;T. Goodrow
通讯作者：
S. Y. Zhang;Andres J Klein-Szanto;E. Sauter;M. Shafarenko;S. Mitsunaga;T. Nobori;D. Carson;J. Ridge;T. Goodrow
影响因子：
11.2
作者：
R. Craven;W. Cance;E. Liu
通讯作者：
R. Craven;W. Cance;E. Liu
与种系无功能 p16INK4a 等位基因相关的家族性肿瘤综合征。
DOI：
10.1093/jnci/88.20.1489
发表时间：
1996
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Yarbrough,WG;Aprelikova,O;Pei,H;Olshan,AF;Liu,ET
通讯作者：
Liu,ET
影响因子：
11.2
作者：
Takahiro Mori;Koh Miura;T. Aoki;T. Nishihira;Shozo Mori;Yusuke Nakamura
通讯作者：
Takahiro Mori;Koh Miura;T. Aoki;T. Nishihira;Shozo Mori;Yusuke Nakamura