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Cyclin-dependent kinase 12 increases 3' end processing of growth factor-induced c-FOS transcripts.

ABSTRACT: 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.

SUBMITTER: Eifler TT

PROVIDER: S-EPMC4272423 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Cyclin-dependent kinase 12 increases 3' end processing of growth factor-induced c-FOS transcripts.

Eifler Tristan T TT Shao Wei W Bartholomeeusen Koen K Fujinaga Koh K Jäger Stefanie S Johnson Jeff R JR Luo Zeping Z Krogan Nevan J NJ Peterlin B Matija BM

Molecular and cellular biology 20141110 2

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 ...[more]

PMID: 25384976

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Project description:BackgroundCyclin-dependent kinase 12 (CDK12) loss occurs in 3-7% of metastatic prostate cancer patients and is characterized by a genomic instability signature, but the clinical implications of CDK12 loss are not well established.ObjectiveTo determine the clinical course of patients with CDK12 mutant advanced prostate cancer compared with other genomic subtypes.Design, setting, and participantsA retrospective analysis of data from three academic medical centers, including 317 patients with advanced prostate cancer and prior next-generation sequencing from tumor tissue (n?=?172) or circulating tumor DNA (n?=?145), was performed. Forty-six patients had CDK12 mutations; 34 had biallelic CDK12 loss (79%).Outcome measurements and statistical analysisPatients were stratified by mutation status (CDK12, homologous recombination deficiency [HRD; BRCA1/2 and ATM], TP53, and other cohort). The Kaplan-Meier method was used to evaluate time to event outcomes: time to development of metastatic disease, time to development of castration resistance, and time to prostate-specific antigen (PSA) progression after first-line androgen receptor pathway inhibitor (ARPI) therapy in a patient subset.Results and limitationsThe median follow-up was 66.6 mo. Patients with CDK12 mutant prostate cancer exhibited shorter time to metastasis (median?=?34.9 mo, p?=? 0.004) and development of castration-resistant disease (median = 32.7 mo, p?<? 0.001), compared with other genomic subtypes, with shorter time to PSA progression on first-line ARPI treatment of metastatic castration-resistant disease (median = 3.6 mo, p?=? 0.0219). CDK12 mutant patients did not have overall shorter time on treatment compared with other mutation subgroups, and CDK12 status did not demonstrate statistical significance in multivariate analysis. Limitations include variable center-dependent practice patterns and heterogeneity due to combining tumor and liquid biopsy data.ConclusionsOur data suggest that advanced prostate cancers harboring CDK12 mutations display aggressive clinical behavior, underscoring the need to fully delineate the molecular and clinical characteristics, and appropriate therapeutic approaches for distinct subtypes of advanced prostate cancers.Patient summaryIn this report, we evaluate the clinical characteristics and outcomes of patients with prostate cancer and CDK12 mutation in their tumors. These patients seem to have more aggressive disease, with more high-grade Gleason ?8 cancers and shorter time to developing metastatic cancer. Cases of advanced CDK12-mutated prostate cancer may warrant consideration of therapy intensification or combination approaches.

Dataset Information

Cyclin-dependent kinase 12 increases 3' end processing of growth factor-induced c-FOS transcripts.

Publications

Cyclin-dependent kinase 12 increases 3' end processing of growth factor-induced c-FOS transcripts.

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