Np95 is regulated by E1A during mitotic reactivation of terminally differentiated cells and is essential for S phase entry

被引:81
作者
Bonapace, IM
Latella, L
Papait, R
Nicassio, F
Sacco, A
Muto, M
Crescenzi, M
Di Fiore, PP
机构
[1] FIRC Inst Mol Oncol, I-50134 Florence, Italy
[2] Univ Insubria, Dipartimento Biol Strutturale & Funz, I-21052 Busto Arsizio, Italy
[3] European Inst Oncol, I-20141 Milan, Italy
[4] Ist Super Sanita, Comparat Toxicol & Ecotoxicol Lab, I-00161 Rome, Italy
[5] Natl Inst Radiol Sci, Div Biol & Oncol, Inage Ku, Chiba 2638555, Japan
[6] Univ Milan, Dipartimento Med Chirurg & Odontoiatria, I-20122 Milan, Italy
关键词
Np95; cell cycle; E1A; pRb; cycE-cdk2;
D O I
10.1083/jcb.200201025
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Terminal differentiation exerts a remarkably tight control on cell proliferation. However, the oncogenic products of DNA tumor viruses, such as adenovirus E1A, can force postmitotic cells to proliferate, thus representing a powerful tool to study progression into S phase. In this study, we identified the gene encoding Np95, a murine nuclear phosphoprotein, as an early target of E1A-induced transcriptional events. In terminally differentiated (TD) cells, the activation of Np95 was specifically induced by El A, but not by overexpression of E2F-1 or of the cyclin E (cycE)-cyclin-dependent kinase 2 (cdk2) complex. In addition, the concomitant expression of Np95 and of cycE-cdk2 was alone sufficient to induce S phase in TD cells. In NIH-3T3 cells, the expression of Np95 was tightly regulated during the cell cycle, and its functional ablation resulted in abrogation of DNA synthesis. Thus, expression of Np95 is essential for S phase entry. Previous evidence suggested that El A, in addition to its well characterized effects on the pRb/E2F-1 pathway, activates a parallel and complementary pathway that is also required for the reentry in S phase of TD cells (Tiainen, M., D. Spitkousky, P. Jansen-Durr, A. Sacchi, and M. Crescenzi. 1996. Mol. Cell. Biol. 16:5302-5312). From our results, Np95 appears to possess all the characteristics to represent the first molecular determinant identified in this pathway.
引用
收藏
页码:909 / 914
页数:6
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