Research ArticleInflammation

CDK12-mediated transcriptional regulation of noncanonical NF-κB components is essential for signaling

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Sci. Signal.  31 Jul 2018:
Vol. 11, Issue 541, eaam8216
DOI: 10.1126/scisignal.aam8216

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CDK12 promotes inflammation

Activating mutations in components of the noncanonical nuclear factor κB (NF-κB) signaling pathway are implicated in various cancers, and ligands that stimulate this pathway are increased in abundance in autoimmune inflammation, which makes this pathway an attractive therapeutic target. By combining a phenotypic screen with chemoproteomics analysis, Henry et al. found a compound that inhibited noncanonical NF-κB signaling by targeting cyclin-dependent kinase 12 (CDK12). By phosphorylating RNA polymerase II, CDK12 enables expression of the kinase NIK, which is required to stimulate the noncanonical NF-κB pathway. Together, these data suggest that CDK12 inhibitors may have therapeutic value in cancer and inflammatory disease.

Abstract

Members of the family of nuclear factor κB (NF-κB) transcription factors are critical for multiple cellular processes, including regulating innate and adaptive immune responses, cell proliferation, and cell survival. Canonical NF-κB complexes are retained in the cytoplasm by the inhibitory protein IκBα, whereas noncanonical NF-κB complexes are retained by p100. Although activation of canonical NF-κB signaling through the IκBα kinase complex is well studied, few regulators of the NF-κB–inducing kinase (NIK)–dependent processing of noncanonical p100 to p52 and the subsequent nuclear translocation of p52 have been identified. We discovered a role for cyclin-dependent kinase 12 (CDK12) in transcriptionally regulating the noncanonical NF-κB pathway. High-content phenotypic screening identified the compound 919278 as a specific inhibitor of the lymphotoxin β receptor (LTβR), and tumor necrosis factor (TNF) receptor superfamily member 12A (FN14)–dependent nuclear translocation of p52, but not of the TNF-α receptor–mediated nuclear translocation of p65. Chemoproteomics identified CDK12 as the target of 919278. CDK12 inhibition by 919278, the CDK inhibitor THZ1, or siRNA-mediated knockdown resulted in similar global transcriptional changes and prevented the LTβR- and FN14-dependent expression of MAP3K14 (which encodes NIK) as well as NIK accumulation by reducing phosphorylation of the carboxyl-terminal domain of RNA polymerase II. By coupling a phenotypic screen with chemoproteomics, we identified a pathway for the activation of the noncanonical NF-κB pathway that could serve as a therapeutic target in autoimmunity and cancer.

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