title: Proliferative and antiapoptotic signaling stimulated by nuclear-localized PDK1 results in oncogenesis.
abstract: Enhanced activation of phosphoinositide 3-kinase (PI3K) is a hallmark of many human tumors because it promotes cell proliferation and survival through several mechanisms. One of these mechanisms is the phosphorylation of the serine and threonine kinase Akt at the cytosolic side of the plasma membrane by phosphoinositide-dependent protein kinase 1 (PDK1), which is recruited and activated by binding to the phosphoinositides produced by PI3K. We previously demonstrated increased nuclear accumulation of PDK1 in cells with enhanced PI3K activity. We report that nuclear PDK1 promoted cell proliferation by suppressing FOXO3A-dependent transcription of the gene encoding p27Kip1 (an inhibitor of cell cycle progression), whereas it enhanced cell survival by inhibiting the activation of c-Jun amino-terminal kinase. Cells with nuclear-localized PDK1 showed anchorage-independent growth, and when injected into mice, these cells induced the formation of solid tumors. In human prostate tumors, cytoplasmic localization of PDK1 correlated only with early-stage, low-risk tumors, whereas nuclear PDK1 localization correlated with high-risk tumors. Together, our findings suggest a role for nuclear-translocated PDK1 in oncogenic cellular transformation and tumor progression in mice and humans.
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Chintan K
authors.initials: CK
authors.lastname: Kikani
authors.forename: Erik V
authors.initials: EV
authors.lastname: Verona
authors.forename: Jiyoon
authors.initials: J
authors.lastname: Ryu
authors.forename: Yanying
authors.initials: Y
authors.lastname: Shen
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Ye
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.forename: Ziliang
authors.initials: Z
authors.lastname: Qian
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakaue
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakamura
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.forename: Qunsheng
authors.initials: Q
authors.lastname: Ji
authors.forename: Wataru
authors.initials: W
authors.lastname: Ogawa
authors.forename: Lu-Zhe
authors.initials: LZ
authors.lastname: Sun
authors.forename: Lily Q
authors.initials: LQ
authors.lastname: Dong
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010735:Phosphoglycerate Kinase / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D010735:Phosphoglycerate Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; C528165:Pgk1 protein, mouse