The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor.
Growth factor withdrawal results in the termination of factor-dependent transcription. One transcript that declines rapidly following growth factor deprivation of hematopoietic cells is the serine/threonine kinase pim-2. When constitutively expressed, Pim-2 conferred long-term resistance to a variety of apoptotic stimuli including growth factor withdrawal and endogenous levels of Pim-2 contributed to growth factor-mediated apoptotic resistance. Pim-2 expression maintained cell size and mitochondrial potential independently of the PI3K/Akt/TOR pathway. Pim-2-dependent maintenance of cell size and survival correlated with its ability to maintain rapamycin-resistant phosphorylation of the translational repressor 4E-BP1 and phosphorylation of the BH3 protein BAD. These results establish Pim-2 as a direct link between growth factor-induced transcription and a novel, kinase-dependent pathway that promotes cell-autonomous survival.
Fox
Casey J
CJ
Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania 19104, USA.
Hammerman
Peter S
PS
Cinalli
Ryan M
RM
Master
Stephen R
SR
Chodosh
Lewis A
LA
Thompson
Craig B
CB
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D007377:Interleukin-3 / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D019076:Transgenes
D000903:Antibiotics, Antineoplastic; D007377:Interleukin-3; D007773:Lactates; C094167:Pim2 protein, mouse; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D019284:Thapsigargin; D017346:Protein Serine-Threonine Kinases; D019311:Staurosporine; D005947:Glucose; D020123:Sirolimus