Identification of 24p3 as a direct target of Foxo3a regulated by interleukin-3 through the phosphoinositide 3-kinase/Akt pathway.
Pro-apoptotic protein 24p3, a member of lipocalin family, is induced upon interleukin-3 (IL-3) deprivation and plays a pivotal role in induction of apoptosis in hematopoietic cells. However, the molecular mechanism by which IL-3 regulates 24p3 expression remains largely unknown. Here, we show that 24p3 is a direct target of Foxo3a and that phosphoinositide 3-kinase (PI3K)/Akt mediates IL-3-repressed 24p3 through regulation of Foxo3a. Inhibition of the PI3K/Akt (but not MAPK) pathway induced 24p3 expression and programmed cell death in FL5.12 cells. Furthermore, constitutively active Akt largely attenuated 24p3 expression and apoptosis in response to IL-3 withdrawal. Foxo3a directly bound to the 24p3 promoter and induced promoter activity. Akt abrogated wild-type Foxo3a-induced (but not Akt-non-phosphorylatable Foxo3a3A-induced) 24p3 expression and promoter activity. Therefore, these data indicate for the first time that 24p3 is a Foxo3a target gene and that PI3K/Akt (but not MAPK) mediates IL-3-regulated 24p3 expression in hematopoietic cells.
Park
Sungman
S
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Guo
Jianping
J
Kim
Donghwa
D
Cheng
Jin Q
JQ
D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*
D000209:Acute-Phase Proteins; D051858:Forkhead Transcription Factors; D007377:Interleukin-3; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C071332:Lcn2 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt