Ribosomal subunit kinase-2 is required for growth factor-stimulated transcription of the c-Fos gene.
Ribosomal subunit kinases (Rsk) have been implicated in the regulation of transcription by phosphorylating and thereby activating numerous transcription factors, such as c-Fos, cAMP responsive element binding protein (CREB), and nuclear receptors. Here we describe the generation and characterization of immortalized embryonic fibroblast cell lines from mice in which the Rsk-2 gene was disrupted by homologous recombinant gene targeting. Rsk-2-deficient (knockout or KO) cell lines have no detectable Rsk-2 protein, whereas Rsk-1 expression is unaltered as compared with cell lines derived from wild-type control mice. KO cells exhibit a major reduction in platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF)-1-stimulated expression of the immediate-early gene c-Fos. This results primarily from a reduced transcriptional activation of the ternary complex factor Elk-1 and reduced activation of the serum response factor. The reduced Elk-1 activation in KO cells occurs despite normal activation of the mitogen-activated protein kinase pathway and normal PDGF- and IGF-1-stimulated Elk-1 phosphorylation. By contrast, PDGF- and IGF-1-stimulated phosphorylation and transcriptional activation of CREB is unaltered in KO cells. Thus Rsk-2 is required for growth factor-stimulated expression of c-Fos and transcriptional activation of Elk-1 and the serum response factor, but not for activation of CREB or the mitogen-activated protein kinase pathway in response to PDGF and IGF-1 stimulation.
Bruning
J C
JC
Klinik II und Poliklinik für Innere Medizin and Center of Molecular Medicine der Universität zu Köln, Joseph Stelzmann Strasse 9, 50931 Cologne, Germany.
Gillette
J A
JA
Zhao
Y
Y
Bjorbaeck
C
C
Kotzka
J
J
Knebel
B
B
Avci
H
H
Hanstein
B
B
Lingohr
P
P
Moller
D E
DE
Krone
W
W
Kahn
C R
CR
Muller-Wieland
D
D
D016475:3T3 Cells; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D017781:Genes, Immediate-Early / Q000235:genetics; D016762:Genes, fos / Q000235:genetics*; D006133:Growth Substances / Q000096:biosynthesis*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases / Q000502:physiology*; D026362:Serum Response Factor; D013997:Time Factors; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D050807:ets-Domain Protein Elk-1
D004268:DNA-Binding Proteins; C494113:Elk1 protein, mouse; D006133:Growth Substances; D009687:Nuclear Proteins; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D026362:Serum Response Factor; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D007334:Insulin-Like Growth Factor I; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D020928:Mitogen-Activated Protein Kinases