PIM-2 is an independent regulator of chondrocyte survival and autophagy in the epiphyseal growth plate.
The overall goal of the investigation was to examine the activity and role of the PIM serine/threonine protein kinases in the growth plate. We showed for the first time that PIM-2 was highly expressed in epiphyseal chondrocytes and that the kinase was required for critical activities linked to cell survival. These activities were independent of those mediated by Akt-1. It was noted that PIM-2 protected chondrocytes from rapamycin sensitized (TOR inhibited) cell death. Since inhibition of mTOR caused autophagy, we examined the autophagic response of PIM-2 silenced cells. We showed that PIM-2 promoted expression and organization of autophagic proteins LC3, and Beclin-1 and enhanced lysosomal acidification. At the same time, PIM-2 modulated the activity of a key regulator of apoptosis, BAD. Since BAD inhibition and Beclin-1 expression activated autophagy, it is likely that induction of the autophagic pathway would serve to inhibit apoptosis and preserve the life of the terminally differentiated chondrocyte. We conclude that PIM-2 regulates a new intermediate stage in the differentiation pathway, the induction of autophagy.
Bohensky
Jolene
J
Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Shapiro
Irving M
IM
Leshinsky
Serge
S
Watanabe
Hitoshi
H
Srinivas
Vickram
V
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000502:physiology*; D001483:Base Sequence; D000071186:Beclin-1; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D006132:Growth Plate / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D017931:DNA Primers; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C094167:Pim2 protein, mouse; D011506:Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C514862:Akt1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus