title: Programmed anuclear cell death delimits platelet life span.
abstract: Platelets are anuclear cytoplasmic fragments essential for blood clotting and wound healing. Despite much speculation, the factors determining their life span in the circulation are unknown. We show here that an intrinsic program for apoptosis controls platelet survival and dictates their life span. Pro-survival Bcl-x(L) constrains the pro-apoptotic activity of Bak to maintain platelet survival, but as Bcl-x(L) degrades, aged platelets are primed for cell death. Genetic ablation or pharmacological inactivation of Bcl-x(L) reduces platelet half-life and causes thrombocytopenia in a dose-dependent manner. Deletion of Bak corrects these defects, and platelets from Bak-deficient mice live longer than normal. Thus, platelets are, by default, genetically programmed to die by apoptosis. The antagonistic balance between Bcl-x(L) and Bak constitutes a molecular clock that determines platelet life span: this represents an important paradigm for cellular homeostasis, and has profound implications for the diagnosis and treatment of disorders that affect platelet number and function.
authors: Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
authors: Kylie D
authors: KD
authors: Mason
authors: Marina R
authors: MR
authors: Carpinelli
authors: Jamie I
authors: JI
authors: Fletcher
authors: Janelle E
authors: JE
authors: Collinge
authors: Adrienne A
authors: AA
authors: Hilton
authors: Sarah
authors: S
authors: Ellis
authors: Priscilla N
authors: PN
authors: Kelly
authors: Paul G
authors: PG
authors: Ekert
authors: Donald
authors: D
authors: Metcalf
authors: Andrew W
authors: AW
authors: Roberts
authors: David C S
authors: DC
authors: Huang
authors: Benjamin T
authors: BT
authors: Kile
mesh_terms: D000818:Animals; D017209:Apoptosis; D032701:Biomimetics; D001713:Biphenyl Compounds / Q000494:pharmacology; D001792:Blood Platelets / Q000166:cytology*; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D003433:Crosses, Genetic; D005038:Ethylnitrosourea / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D016296:Mutagenesis / Q000187:drug effects; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013449:Sulfonamides / Q000494:pharmacology; D013921:Thrombocytopenia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C501332:ABT-737; C494773:Bak1 protein, mouse; C494812:Bcl2l1 protein, mouse; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D020169:Caspases; D005038:Ethylnitrosourea