Cell death provoked by loss of interleukin-3 signaling is independent of Bad, Bim, and PI3 kinase, but depends in part on Puma.
Growth and survival of hematopoietic cells is regulated by growth factors and cytokines, such as interleukin 3 (IL-3). When cytokine is removed, cells dependent on IL-3 kill themselves by a mechanism that is inhibited by overexpression of Bcl-2 and is likely to be mediated by proapoptotic Bcl-2 family members. Bad and Bim are 2 such BH3-only Bcl-2 family members that have been implicated as key initiators in apoptosis following growth factor withdrawal, particularly in IL-3-dependent cells. To test the role of Bad, Bim, and other proapoptotic Bcl-2 family members in IL-3 withdrawal-induced apoptosis, we generated IL-3-dependent cell lines from mice lacking the genes for Bad, Bim, Puma, both Bad and Bim, and both Bax and Bak. Surprisingly, Bad was not required for cell death following IL-3 withdrawal, suggesting changes to phosphorylation of Bad play only a minor role in apoptosis in this system. Deletion of Bim also had no effect, but cells lacking Puma survived and formed colonies when IL-3 was restored. Inhibition of the PI3 kinase pathway promoted apoptosis in the presence or absence of IL-3 and did not require Bad, Bim, or Puma, suggesting IL-3 receptor survival signals and PI3 kinase survival signals are independent.
Ekert
Paul G
PG
Children's Cancer Centre, Murdoch Children's Research Centre, Royal Children's Hospital, Flemington Rd, Parkville, Victoria 3052, Australia. paul.ekert@rch.org.au
Jabbour
Anissa M
AM
Manoharan
Anand
A
Heraud
Jacki E
JE
Yu
Jai
J
Pakusch
Miha
M
Michalak
Ewa M
EM
Kelly
Priscilla N
PN
Callus
Bernard
B
Kiefer
Thomas
T
Verhagen
Anne
A
Silke
John
J
Strasser
Andreas
A
Borner
Christoph
C
Vaux
David L
DL
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death / Q000502:physiology*; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D007377:Interleukin-3 / Q000494:pharmacology / Q000502:physiology*; D008565:Membrane Proteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000502:physiology; D051025:bcl-Associated Death Protein / Q000172:deficiency / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; C494827:Bax protein, mouse; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D007377:Interleukin-3; D008565:Membrane Proteins; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D019869:Phosphatidylinositol 3-Kinases