-
39浏览
-
0点赞
-
0收藏
-
0分享
-
85下载
-
0评论
-
引用
期刊论文
Identification of mutations that disrupt phosphorylation-dependent nuclearexport of cyclin D1S Benzeno1, F Lu1, M Guo2, O Barbash1, F Zhang1,3, JG Herman2, PS Klein3, A Rustgi1,3 and
Oncogene (2006)25, 6291-6303,-0001,():
Although cyclin D1is overexpressed in a significantnumber of human cancers, overexpression alone isinsufficient to promote tumorigenesis. In vitro studieshave revealed that inhibition of cyclin D1nuclea r exportunmasks its neoplastic potential. Cyclin D1nuclea rexport depends upon phosphorylation of a C-terminalresidue, threonine 286, (Thr-286) which in turn promotesassociation with the nuclear exportin, CRM1. Mutationof Thr-286 to a non-phosphorylatable residue results in aconstitutively nuclear cyclin D1prote in with significantlyincreased oncogenic potential. To determine whethercyclin D1is subject to mutations that inhibit its nuclearexport in human cancer, we have sequenced exon 5 ofcyclin D1in primary esophageal carcinoma samples andin cell lines derived from esophageal cancer. Our workreveals that cyclin D1is subject to mutations in primaryhuman cancer. The mutations identified specificallydisrupt phosphorylation of cyclin D1at Thr-286, therebyenforcing nuclear accumulation of cyclin D1. Throughcharacterization of these mutants, we also define an acidicresidue within the C-terminus of cyclin D1that isnecessary for recognition and phosphorylation of cyclinD1by glycogen synthase kinase-3 beta. Finally, throughconstruction of compound mutants, we demonstrate thatcell transformation by the cancer-derived cyclin D1allelescorrelates with their ability to associate with and activateCDK4. Our data reveal that cyclin D1is subject tomutations in primary human cancer that specificallydisrupt phosphorylation-dependent nuclear export ofcyclin D1and suggest that such mutations contribute tothe genesis and progression of neoplastic growth.Oncogene (2006) 25, 6291–6303. doi:10.1038/sj.onc.1209644;published online 29 May 2006
【免责声明】以下全部内容由[鲁凤民]上传于[2010年10月18日 14时17分17秒],版权归原创者所有。本文仅代表作者本人观点,与本网站无关。本网站对文中陈述、观点判断保持中立,不对所包含内容的准确性、可靠性或完整性提供任何明示或暗示的保证。请读者仅作参考,并请自行承担全部责任。
本学者其他成果
同领域成果