CDK12-mediated transcriptional regulation of noncanonical NF-{kappa}B components is essential for signaling

Members of the family of nuclear factor B (NF-B) transcription factors are critical for multiple cellular processes, including regulating innate and adaptive immune responses, cell proliferation, and cell survival. Canonical NF-B complexes are retained in the cytoplasm by the inhibitory protein IBα, whereas noncanonical NF-B complexes are retained by p100. Although activation of canonical NF-B signaling through the IBα kinase complex is well studied, few regulators of the NF-B–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-B 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 cou...

Source: Signal Transduction Knowledge Environment - July 31, 2018 Category: Science Authors: Henry, K. L., Kellner, D., Bajrami, B., Anderson, J. E., Beyna, M., Bhisetti, G., Cameron, T., Capacci, A. G., Bertolotti-Ciarlet, A., Feng, J., Gao, B., Hopkins, B., Jenkins, T., Li, K., May-Dracka, T., Murugan, P., Wei, R., Zeng, W., Allaire, N., Buckle Tags: STKE Research Articles Source Type: news