GSK-3beta-dependent destabilization of cyclin D1 mediates replicational stress-induced arrest of cell cycle.
Chemotherapeutic agents are well known to induce growth arrest of cancerous cells by inducing DNA damage/replicational stress and engaging cellular apoptotic machinery. Our studies on hydroxyurea (HU) recognized cyclin D1 destabilization as the initiator of growth arrest at G(1)/S-phase independent of other cell cycle regulators. Cyclin D1 degradation was associated with its phosphorylation at Thr286 by glycogen synthase kinase-3beta and inactivation of Akt kinase. Overexpression of the cyclin D1(T286A) mutant, or constitutively active Akt, conferred stability to cyclin D1 and helped bypass cell cycle arrest. Thus, growth arrest by HU seems to involve destabilization of cyclin D1 in addition to its well-established role as ribonucleotide reductase inhibitor.
Mukherji
Atish
A
Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110 067, India.
Janbandhu
Vaibhao C
VC
Kumar
Vijay
V
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism*; D004261:DNA Replication; D016193:G1 Phase; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D051379:Mice; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016196:S Phase
D000970:Antineoplastic Agents; D019938:Cyclin D1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D006918:Hydroxyurea