The Rb-family protein p107 inhibits translation by a PDK1-dependent mechanism

Abstract

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.