ERK-dependent phosphorylation of the transcription initiation factor TIF-IA is required for RNA polymerase I transcription and cell growth.
Phosphorylation of transcription factors by mitogen-activated protein kinase (MAPK) cascades links cell signaling with the control of gene expression. Here we show that growth factors induce rRNA synthesis by activating MAPK-dependent signaling cascades that target the RNA polymerase I-specific transcription initiation factor TIF-IA. Activation of TIF-IA and ribosomal gene transcription is sensitive to PD98059, indicating that TIF-IA is targeted by MAPK in vivo. Phosphopeptide mapping and mutational analysis reveals two serine residues (S633 and S649) that are phosphorylated by ERK and RSK kinases. Replacement of S649 by alanine inactivates TIF-IA, inhibits pre-rRNA synthesis, and retards cell growth. The results provide a link between growth factor signaling, ribosome production, and cell growth, and may have a major impact on the mechanism of cell transformation.
Zhao
Jian
J
Division of Molecular Biology of the Cell II, German Cancer Research Center, D-69120, Heidelberg, Germany.
Yuan
Xuejun
X
Frödin
Morten
M
Grummt
Ingrid
I
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008934:Mitogens / Q000494:pharmacology; D008969:Molecular Sequence Data; D010766:Phosphorylation; D035463:Pol1 Transcription Initiation Complex Proteins; D011494:Protein Kinases / Q000378:metabolism; D012318:RNA Polymerase I / Q000378:metabolism*; D012335:RNA, Ribosomal / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D008934:Mitogens; D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; C428423:RRN3 protein, human; D011994:Recombinant Proteins; D014157:Transcription Factors; D011494:Protein Kinases; D019893:Ribosomal Protein S6 Kinases; D020928:Mitogen-Activated Protein Kinases; D012318:RNA Polymerase I