Tuberous sclerosis causing mutants of the TSC2 gene product affect proliferation and p27 expression
Tuberous sclerosis causing mutants of the TSC2 gene product affect proliferation and p27 expression
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结节性硬化症导致 TSC2 基因产物突变影响增殖和 p27 表达
DOI：
10.1038/sj.onc.1204627
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发表时间：
2001
期刊：
影响因子：
8
通讯作者：
M. Hengstschläger
中科院分区：
文献类型：
--
作者：
T. Soucek;M. Rosner;A. Miloloza;M. Kubista;J. Cheadle;J. Sampson;M. Hengstschläger
常染色体显性遗传疾病结节性硬化症（TSC）是由染色体9 q34上编码hamartin的TSC 1或染色体16p13.3上编码tuberin的TSC 2突变引起的。TSC的特征在于在受影响患者的许多器官中发生的错构瘤，并且这些错构瘤被认为可能是由增殖控制缺陷引起的。虽然这两种TSC蛋白的真正生物化学功能尚未阐明，但一系列独立的研究表明，在人类、啮齿动物和果蝇细胞中，受调节的错构蛋白或块茎蛋白表达导致增殖/细胞周期失调。为了支持块茎素作为肿瘤抑制剂的作用，已经显示TSC 2的异位过表达降低哺乳动物细胞的增殖速率。此外，已经证明TSC 2的过表达触发细胞周期蛋白依赖性激酶抑制剂p27的上调。我们报道了三种不同的自然发生的和TSC引起的TSC 2基因突变既不消除tuberin的抗增殖能力，也不消除tuberin对p27表达的影响。这些数据首次提供了强有力的证据，即增殖失调和/或p27上调不太可能是TSC中错构瘤发展的主要/唯一机制。这些结果需要重新评估以前的假设TSC的发病机制。
The autosomal dominant disease tuberous sclerosis (TSC) is caused by mutations in either TSC1 on chromosome 9q34, encoding hamartin, or TSC2 on chromosome 16p13.3, encoding tuberin. TSC is characterized by hamartomas that occur in many organs of affected patients and these have been considered to likely result from defects in proliferation control. Although the true biochemical functions of the two TSC proteins have not been clarified, a series of independent investigations demonstrated that modulated hamartin or tuberin expression cause deregulation of proliferation/cell cycle in human, rodent and Drosophila cells. In support of tuberin acting as a tumor suppressor, ectopic overexpression of TSC2 has been shown to decrease proliferation rates of mammalian cells. Furthermore, overexpression of TSC2 has been demonstrated to trigger upregulation of the cyclin-dependent kinase inhibitor p27. We report that three different naturally occurring and TSC causing mutations within the TSC2 gene elliminate neither the anti-proliferative capacity of tuberin nor tuberin's effects on p27 expression. For the first time these data provide strong evidence that deregulation of proliferation and/or upregulation of p27 are not likely to be the primary/only mechanisms of hamartoma development in TSC. These results demand reassessment of previous hypotheses of the pathogenesis of TSC.
DOI：
10.1073/pnas.91.24.11413
发表时间：
1994-11-22
影响因子：
11.1
作者：
YEUNG, RS;XIAO, GH;KNUDSON, AG
通讯作者：
KNUDSON, AG
在缺乏 TSC2 基因产物的全胚胎培养物中持续心肌细胞 DNA 合成。
DOI：
10.1152/ajpheart.1997.273.3.h1619
发表时间：
1997
期刊：
The American journal of physiology
影响因子：
--
作者：
Pajak,L;Jin,F;Xiao,GH;Soonpaa,MH;Field,LJ;Yeung,RS
通讯作者：
Yeung,RS
DOI：
10.1073/pnas.96.21.11866
发表时间：
1999-10-12
影响因子：
11.1
作者：
Aprelikova, ON;Fang, BS;Liu, ET
通讯作者：
Liu, ET