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© The Rockefeller University Press, 0021-9525/2002/6/909 $5.00
The Journal of Cell Biology, Volume 157, Number 6, June 10, 2002 909-914

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

¹ The FIRC Institute for Molecular Oncology, 20134 Milan, Italy
² Dipartimento di Biologia Strutturale e Funzionale, Universita' dell'Insubria, Busto Arsizio, 21052, Italy
³ Laboratory of Comparative Toxicology and Ecotoxicology, Istituto Superiore di Sanità, 00161 Rome, Italy
⁴ European Institute of Oncology, 20141, Milan, Italy
⁵ Division of Biology and Oncology, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan
⁶ Dipartimento di Medicina Chirurgia ed Odontoiatria, Universita' degli Studi di Milano, 20122 Milan, Italy

Address correspondence to Pier Paolo Di Fiore, The FIRC Institute for Molecular Oncology, Via Serio 21, 20134 Milan, Italy. Tel.: 39-02-57489855. Fax: 39-02-57489851. E-mail: difiore{at}ifom-firc.it

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 E1A, 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 E1A, 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-Dürr, 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.

Key Words: Np95; cell cycle; E1A; pRb; cycE–cdk2

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