期刊
EXPERIMENTAL CELL RESEARCH
卷 315, 期 18, 页码 3152-3162出版社
ELSEVIER INC
DOI: 10.1016/j.yexcr.2009.07.009
关键词
TIS21(/BTG2/PC3); Skp2; Ubiquitination; FoxM1; BTG/TOB family; APRO gene
资金
- Korea Science and Engineering Foundation [R01-2006-000-10311-0, M10756040001-08N5604-00110, 2008-0058591]
- National Research Foundation of Korea [R01-2006-000-10311-0, 2008-0058591] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
TIS21(/BTG2/PC3) has been shown to work as a pan-cell cycle inhibitor and a negative regulator of cyclin B1/cdk1 and forkhead box M1 (center dot)(FoxM1). Moreover, loss of TIS21 expression has been suggested as an early event in carcinogenesis of thymus, prostate, kidney, and liver. However, there is no report yet what regulates the in vivo stability of TIS21 protein. Here, TIS21 was found to be a target of ubiquitin ligase, S phase kinase associated protein 2 (Skp2), the expression of which was regulated by FoxM1 Leucine rich re eat (LRR) domain of Skp2 could bind to TIS21 C-terminus and facilitated TIS21 degradation via ubiquitin-proteasome pathway. Skp2 without LRR and C-terminus deleted TIS21 (TIS21 Delta C) failed to interact with each other, and failure of their interaction prolonged half-life of TIS21 protein. Furthermore, in vivo function of TIS21, inhibition of cell growth, was regulated by expressions of Skp2 and FoxM1; It was significantly enhanced by knock down of Skp2 expression in the TIS21 adenovirus infected cells, whereas it was significantly ameliorated by co-expression of FoxM1 with TIS21. These data indicate that TIS21 is a novel target of SCF-Skp2 ubiquitin ligase, which is regulated by expression of FoxM1. (C) 2009 Elsevier Inc. All rights reserved.
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