Signal transducer and activator of transcription 3 and the phosphatidylinositol 3-kinase regulatory subunits p55[alpha] and p50[alpha] regulate autophagy in vivo

Mammary gland involution involves a process that includes one of the most dramatic examples of cell death in an adult mammalian organism. We have previously shown that signal transducer and activator of transcription 3 (Stat3) regulates a lysosomal pathway of cell death in the first 48 h of involution and induces lysosome leakiness in mammary epithelial cells. Interestingly, Stat3 is associated also with the striking induction of autophagy that occurs concomitantly with cell death, presumably as a transient survival mechanism. The phosphatidylinositol 3-kinase regulatory subunits p55[alpha] and p50[alpha] are dramatically and specifically upregulated at the transcriptional level by Stat3 at the onset of involution. We show here that ablation of either Stat3 or p55[alpha]/p50[alpha] in vivo affects autophagy during involution. We used two different cell culture models (normal mammary epithelial cells and mouse embryonic fibroblasts) to further investigate the role of p55[alpha]/p50[alpha] in autophagy regulation. Our results demonstrate a direct role for p55[alpha]/p50[alpha] as inhibitors of autophagy mediated by p85[alpha]. Thus, Stat3 and its downstream targets p55[alpha]/p50[alpha] are key regulators of the balance between autophagy and cell death in vivo.