HBx protein modulates PI3K/Akt pathway to overcome genotoxic stress-induced destabilization of cyclin D1 and arrest of cell cycle.
Growth arrest represents an innate barrier to carcinogenesis. DNA damage and replicational stress are known to induce growth arrest and apoptotic death to avert genomic instability and consequently carcinogenesis. In this study, working on the genotoxic stress induced by hydroxyurea and methylmethanesulfone, we observed a growth arrest at G1/S-phase that was mediated by destabilization of cyclin D1. The growth arrest was independent of the stability of cdc25A and preceded transcriptional up-regulation of p21(waf1). Cyclin D1 destabilization involved its phosphorylation by GSK-3beta at threonine-286, since overexpression of the kinase-dead mutant of GSK-3beta or cyclin D1T(286A) Inutant conferred stability to cyclin D1. Further, overexpression of cyclin D1(T286A) also helped in bypassing G1/S phase growth arrest. We also observed a rapid inactivation of Akt/PKB kinase in the presence of hydroxyurea. Enforced expression of the constitutively active Akt or viral oncoprotein HBx (Hepatitis B virus X protein) was sufficient to overcome growth arrest, independent of ATR signaling and stabilized cyclin D1. Thus, the present work not only establishes cyclin D1 to be a novel mediator of genotoxic stress signaling, but also explains how a deregulated mitogenic signaling or a viral oncoprotein can help bypass growth arrest.
Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.
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Mukherji
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Janbandhu
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Kumar
D064413:3-Phosphoinositide-Dependent Protein Kinases; D002453:Cell Cycle / Q000502:physiology*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006515:Hepatitis B virus; D006801:Humans; D006918:Hydroxyurea; D008741:Methyl Methanesulfonate; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000378:metabolism
C530104:CCND1 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D019938:Cyclin D1; D008741:Methyl Methanesulfonate; D064413:3-Phosphoinositide-Dependent Protein Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C578562:PDPK1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; D006918:Hydroxyurea