title: PDK1 regulates cell proliferation and cell cycle progression through control of cyclin D1 and p27Kip1 expression.
abstract: PDK1 (3-phosphoinositide-dependent protein kinase 1) is a key mediator of signaling by phosphoinositide 3-kinase. To gain insight into the physiological importance of PDK1 in cell proliferation and cell cycle control, we established immortalized mouse embryonic fibroblasts (MEFs) from mice homozygous for a "floxed" allele of Pdk1 and from wild-type mice. Introduction of Cre recombinase by retrovirus-mediated gene transfer resulted in the depletion of PDK1 in Pdk1(lox/lox) MEFs but not in Pdk1(+/+) MEFs. The insulin-like growth factor-1-induced phosphorylation of various downstream effectors of PDK1, including Akt, glycogen synthase kinase 3, ribosomal protein S6, and p70 S6 kinase, was markedly inhibited in the PDK1-depleted (Pdk1-KO) MEFs. The rate of serum-induced cell proliferation was reduced; progression of the cell cycle from the G(0)-G(1) phase to the S phase was delayed, and cell cycle progression at G(2)-M phase was impaired in Pdk1-KO MEFs. These cells also manifested an increased level of p27(Kip1) expression and a reduced level of cyclin D1 expression during cell cycle progression. The defect in cell cycle progression from the G(0)-G(1) to the S phase in Pdk1-KO MEFs was rescued by forced expression of cyclin D1, whereas rescue of the defect in G(2)-M progression in these cells required both overexpression of cyclin D1 and depletion of p27(Kip1) by RNA interference. These data indicate that PDK1 plays an important role in cell proliferation and cell cycle progression by controlling the expression of both cyclin D1 and p27(Kip1).
authors.affiliation: Department of Internal Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakaue
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nishizawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuki
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Gomi
authors.forename: Eijiro
authors.initials: E
authors.lastname: Watanabe
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hiramatsua
authors.forename: Mimi
authors.initials: M
authors.lastname: Tamamori-Adachi
authors.forename: Shigetaka
authors.initials: S
authors.lastname: Kitajima
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Wataru
authors.initials: W
authors.lastname: Ogawa
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004247:DNA / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009841:Oligonucleotides / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D009841:Oligonucleotides; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases