G0 function of BCL2 and BCL-xL requires BAX, BAK, and p27 phosphorylation by Mirk, revealing a novel role of BAX and BAK in quiescence regulation.
BCL2 and BCL-x(L) facilitate G(0) quiescence by decreasing RNA content and cell size and up-regulating p27 protein, but the precise mechanism is not understood. We investigated the relationship between cell cycle regulation and the anti-apoptosis function of BCL2 and BCL-x(L). Neither caspase inhibition nor abrogation of mitochondria-dependent apoptosis by BAX and BAK deletion fully recapitulated the G(0) effects of BCL2 or BCL-x(L), suggesting that mechanisms in addition to anti-apoptosis are involved in the cell cycle arrest function of BCL2 or BCL-x(L). We found that BCL2 and BCL-x(L) expression in bax(-/-) bak(-/-) cells did not confer cell cycle effects, consistent with the G(0) function of BCL2 and BCL-x(L) being mediated through BAX or BAK. Stabilization of p27 in G(0) in BCL2 or BCL-x(L) cells was due to phosphorylation of p27 at Ser(10) by the kinase Mirk. In bax(-/-) bak(-/-) cells, total p27 and p27 phosphorylated at Ser(10) were elevated. Re-expression of BAX in bax(-/-) bak(-/-) cells and silencing of BAX and BAK in wild type cells confirmed that endogenous BAX and BAK modulated p27. These data revealed a novel role for BAX and BAK in the regulation of G(0) quiescence.
Janumyan
Yelena
Y
Department of Pediatrics, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Cui
Qinghua
Q
Yan
Ling
L
Sansam
Courtney G
CG
Valentin
Mayda
M
Yang
Elizabeth
E
D000818:Animals; D053453:Caspase 9 / Q000378:metabolism; D002453:Cell Cycle; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D051381:Rats; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000502:physiology*; D051020:bcl-X Protein / Q000378:metabolism*; D000097603:Dyrk Kinases
D053453:Caspase 9; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004791:Enzyme Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D000097603:Dyrk Kinases