title: c-ETS1 facilitates G1/S-phase transition by up-regulating cyclin E and CDK2 genes and cooperates with hepatitis B virus X protein for their deregulation.
abstract: Recent studies on the molecular mechanisms responsible for cell cycle deregulation in cancer have puzzled out the role of oncogenes in mediating unscheduled cellular proliferation. This is reminiscence of their activity as proto-oncogenes that drives scheduled cell cycle progression under physiological conditions. Working on the cell cycle regulatory activity of proto-oncogene, we observed that c-ETS1 transcriptionally up-regulated both cyclin E and CDK2 genes, the master regulators of G(1)/S-phase transition. The process was mediated by kinetic coherence of c-ETS1 expression and its recruitment to both promoters during G(1)/S-phase transition. Furthermore, enforced expression of c-ETS1 helped G(0)-arrested cells to progress into G(1)/S-phases apparently due to the activation of cyclin E/CDK2 genes. Physiological induction of c-ETS1 by EGF showed the remodeling of mononucleosomes bound to the c-ETS1 binding site on both promoters during their activation. The exchange of HDAC1 with histone acetyltransferase-p300 was contemporaneous to the chromatin remodeling with consequent increase in histone H3K9 acetylation. Furthermore, the ATP-dependent chromatin remodeler hBRM1 recruitment was also associated with nucleosome remodeling and promoter occupancy of phospho-Ser5 RNA polymerase II. Intriguingly, the activity of the HBx viral oncoprotein was dependent on c-ETS1 in a hepatotropic manner, which led to the activation of cyclin E/CDK2 genes. Thus, cyclin E and CDK2 genes are key physiological effectors of the c-ETS1 proto-oncogene. Furthermore, c-ETS1 is indispensable for the hepatotropic action of HBx in cell cycle deregulation.
authors.affiliation: Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Anup Kumar
authors.initials: AK
authors.lastname: Singh
authors.forename: Manickavinayaham
authors.initials: M
authors.lastname: Swarnalatha
authors.forename: Vijay
authors.initials: V
authors.lastname: Kumar
mesh_terms: D002460:Cell Line; D019927:Cyclin E / Q000235:genetics*; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D009707:Nucleosomes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D000090063:Proto-Oncogene Mas; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D016196:S Phase / Q000187:drug effects / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D019927:Cyclin E; C000715470:MAS1 protein, human; D009707:Nucleosomes; D000090063:Proto-Oncogene Mas; D050784:Proto-Oncogene Protein c-ets-1; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D004815:Epidermal Growth Factor; D051357:Cyclin-Dependent Kinase 2