title: Np95 is regulated by E1A during mitotic reactivation of terminally differentiated cells and is essential for S phase entry.
abstract: 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.
authors.affiliation: The FIRC Institute for Molecular Oncology, 20134 Milan, Italy.
authors.forename: Ian Marc
authors.initials: IM
authors.lastname: Bonapace
authors.forename: Lucia
authors.initials: L
authors.lastname: Latella
authors.forename: Roberto
authors.initials: R
authors.lastname: Papait
authors.forename: Francesco
authors.initials: F
authors.lastname: Nicassio
authors.forename: Alessandra
authors.initials: A
authors.lastname: Sacco
authors.forename: Masahiro
authors.initials: M
authors.lastname: Muto
authors.forename: Marco
authors.initials: M
authors.lastname: Crescenzi
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
mesh_terms: D016475:3T3 Cells; D017500:Adenovirus E1A Proteins / Q000502:physiology*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004279:DNA, Viral / Q000502:physiology; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D007700:Kinetics; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology*; D010750:Phosphoproteins / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016196:S Phase / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases
chemical_list: D017500:Adenovirus E1A Proteins; D022762:CCAAT-Enhancer-Binding Proteins; D019927:Cyclin E; D004279:DNA, Viral; D009687:Nuclear Proteins; D010750:Phosphoproteins; D044767:Ubiquitin-Protein Ligases; C117054:Uhrf1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases