Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation.
tob is a member of an emerging family of genes with antiproliferative function. Tob is rapidly phosphorylated at Ser 152, Ser 154, and Ser 164 by Erk1 and Erk2 upon growth-factor stimulation. Oncogenic Ras-induced transformation and growth-factor-induced cell proliferation are efficiently suppressed by mutant Tob that carries alanines but not glutamates, mimicking phosphoserines, at these sites. Wild-type Tob inhibits cell growth when the three serine residues are not phosphorylated but is less inhibitory when the serines are phosphorylated. Because growth of Rb-deficient cells was not affected by Tob, Tob appears to function upstream of Rb. Intriguingly, cyclin D1 expression is elevated in serum-starved tob(-/-) cells. Reintroduction of wild-type Tob and mutant Tob with serine-to-alanine but not to glutamate mutations on the Erk phosphorylation sites in these cells restores the suppression of cyclin D1 expression. Finally, the S-phase population was significantly increased in serum-starved tob(-/-) cells as compared with that in wild-type cells. Thus, Tob inhibits cell growth by suppressing cyclin D1 expression, which is canceled by Erk1- and Erk2-mediated Tob phosphorylation. We propose that Tob is critically involved in the control of early G(1) progression.
Suzuki
Toru
T
Department of Oncology, Institute of Medical Science, University of Tokyo, Minato-ku 108-8639, Japan.
K-Tsuzuku
Junko
J
Ajima
Rieko
R
Nakamura
Takahisa
T
Yoshida
Yutaka
Y
Yamamoto
Tadashi
T
D016475:3T3 Cells; D000409:Alanine / Q000737:chemistry; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D002453:Cell Cycle; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016193:G1 Phase; D018698:Glutamic Acid / Q000737:chemistry; D005973:Glutamine / Q000737:chemistry; D005982:Glutathione Transferase / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010449:Peptide Mapping; D010766:Phosphorylation; D010768:Phosphoserine / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016192:Resting Phase, Cell Cycle; D016196:S Phase; D012694:Serine / Q000737:chemistry*; D013997:Time Factors; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism*
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D047908:Intracellular Signaling Peptides and Proteins; C490903:Tob1 protein, mouse; D005973:Glutamine; D019938:Cyclin D1; D010768:Phosphoserine; D018698:Glutamic Acid; D012694:Serine; D005982:Glutathione Transferase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D000409:Alanine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one