The Rb-family protein p107 inhibits translation by a PDK1-dependent mechanism.
The Rb family of proteins, which consists of Rb, p107 and p130, are critical regulators of cell proliferation. In addition to their inhibitory effects on cell cycle progression, Rb-family proteins repress transcription by RNA polymerases I and III, and may therefore restrain cell growth. However, it is not known if Rb, p107 or p130 have direct effects on protein synthesis. Here we report that ectopic expression of p107 in rat fibroblasts markedly attenuates the stimulation of mRNA translation and global protein synthesis by serum growth factors. This effect is associated with a reduction in the phosphorylation and activation of the serine-threonine kinases Akt1 and p70 S6 kinase (S6K1), two downstream targets of phosphoinositide-dependent kinase 1 (PDK1). We show that overexpression of p107 interferes with the recruitment of PDK1 to the plasma membrane in response to growth factors. Overexpression of PDK1 restores the defect in translation elicited by p107. These results suggest that p107 restricts cell growth by interfering with the phosphoinositide 3-kinase (PI3K) signaling pathway.
Makris
Constantin
C
Institut de recherches cliniques de Montréal and Department of Pharmacology, University of Montreal, 110 Pine Avenue West, Montreal, Quebec H2W 1R7, Canada.
Voisin
Laure
L
Giasson
Edith
E
Tudan
Christopher
C
Kaplan
David R
DR
Meloche
Sylvain
S
D064413:3-Phosphoinositide-Dependent Protein Kinases; D020816:Amino Acid Motifs; D000818:Animals; D002455:Cell Division; D002460:Cell Line / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005816:Genetic Complementation Test; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000201:enzymology; D014162:Transfection
D064413:3-Phosphoinositide-Dependent Protein Kinases; D016895:Culture Media, Serum-Free; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C494920:Akt1 protein, rat; C578579:Pdpk1 protein, rat; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1