Cyclin-dependent kinase 12 increases 3' end processing of growth factor-induced c-FOS transcripts.
Transcriptional cyclin-dependent kinases (CDKs) regulate RNA polymerase II initiation and elongation as well as cotranscriptional mRNA processing. In this report, we describe an important role for CDK12 in the epidermal growth factor (EGF)-induced c-FOS proto-oncogene expression in mammalian cells. This kinase was found in the exon junction complexes (EJC) together with SR proteins and was thus recruited to RNA polymerase II. In cells depleted of CDK12 or eukaryotic translation initiation factor 4A3 (eIF4A3) from the EJC, EGF induced fewer c-FOS transcripts. In these cells, phosphorylation of serines at position 2 in the C-terminal domain (CTD) of RNA polymerase II, as well as levels of cleavage-stimulating factor 64 (Cstf64) and 73-kDa subunit of cleavage and polyadenylation specificity factor (CPSF73), was reduced at the c-FOS gene. These effects impaired 3' end processing of c-FOS transcripts. Mutant CDK12 proteins lacking their Arg-Ser-rich (RS) domain or just the RS domain alone acted as dominant negative proteins. Thus, CDK12 plays an important role in cotranscriptional processing of c-FOS transcripts.
Department of Medicine, Microbiology and Immunology, University of California at San Francisco, San Francisco, California, USA Tristan.Eifler@ucsf.edu matija.peterlin@ucsf.edu.
Tristan T
TT
Eifler
Department of Medicine, Microbiology and Immunology, University of California at San Francisco, San Francisco, California, USA.
Wei
W
Shao
Department of Medicine, Microbiology and Immunology, University of California at San Francisco, San Francisco, California, USA.
Koen
K
Bartholomeeusen
Department of Medicine, Microbiology and Immunology, University of California at San Francisco, San Francisco, California, USA.
Koh
K
Fujinaga
Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California, USA California Institute for Quantitative Biosciences, QB3, San Francisco, California, USA.
Stefanie
S
Jäger
Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California, USA California Institute for Quantitative Biosciences, QB3, San Francisco, California, USA.
Jeff R
JR
Johnson
Department of Medicine, Microbiology and Immunology, University of California at San Francisco, San Francisco, California, USA.
Zeping
Z
Luo
Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California, USA California Institute for Quantitative Biosciences, QB3, San Francisco, California, USA.
Nevan J
NJ
Krogan
Department of Medicine, Microbiology and Immunology, University of California at San Francisco, San Francisco, California, USA Tristan.Eifler@ucsf.edu matija.peterlin@ucsf.edu.
B Matija
BM
Peterlin
D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics
D036341:Intercellular Signaling Peptides and Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; C447339:CDK12 protein, human; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II