title: Bax-mediated cell death by the Gax homeoprotein requires mitogen activation but is independent of cell cycle activity.
abstract: Tissues with the highest rates of proliferation typically exhibit the highest frequencies of apoptosis, but the mechanisms that coordinate these processes are largely unknown. The homeodomain protein Gax is down-regulated when quiescent cells are stimulated to proliferate, and constitutive Gax expression inhibits cell proliferation in a p21(WAF/CIP)-dependent manner. To understand how mitogen-induced proliferation influences the apoptotic process, we investigated the effects of deregulated Gax expression on cell viability. Forced Gax expression induced apoptosis in mitogen-activated cultures, but quiescent cultures were resistant to cell death. Though mitogen activation was required for apoptosis, neither the cdk inhibitor p21(WAF/CIP) nor the tumor suppressor p53 was required for Gax-induced cell death. Arrest in G1 or S phases of the cell cycle with chemical inhibitors also did not affect apoptosis, further suggesting that Gax-mediated cell death is independent of cell cycle activity. Forced Gax expression led to Bcl-2 down-regulation and Bax up-regulation in mitogen-activated, but not quiescent cultures. Mouse embryonic fibroblasts homozygous null for the Bax gene were refractive to Gax-induced apoptosis, demonstrating the functional significance of this regulation. These data suggest that the homeostatic balance between cell growth and death can be controlled by mitogen-dependent pathways that circumvent the cell cycle to alter Bcl-2 family protein expression.
authors.affiliation: Division of Cardiovascular Research, St Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge Street, Boston, MA 02135, USA.
authors.forename: H
authors.initials: H
authors.lastname: Perlman
authors.forename: M
authors.initials: M
authors.lastname: Sata
authors.forename: A
authors.initials: A
authors.lastname: Le Roux
authors.forename: T W
authors.initials: TW
authors.lastname: Sedlak
authors.forename: D
authors.initials: D
authors.lastname: Branellec
authors.forename: K
authors.initials: K
authors.lastname: Walsh
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D016193:G1 Phase; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006918:Hydroxyurea / Q000494:pharmacology; D008297:Male; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D010641:Phenotype; D011090:Polyenes / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016196:S Phase; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D020123:Sirolimus; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein
chemical_list: C494827:Bax protein, mouse; C494828:Bax protein, rat; C493957:Cdkn1a protein, mouse; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018398:Homeodomain Proteins; C081336:Meox2 protein, rat; D008934:Mitogens; D009124:Muscle Proteins; D011090:Polyenes; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D012710:Serum Albumin, Bovine; D020123:Sirolimus; D006918:Hydroxyurea