CDK12-mediated transcriptional regulation of noncanonical NF-κB components is essential for signaling PMID: 30065029

ADC Targets in Oncology

2026-04-10

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

Sci Signal. 2018 Jul 31;11(541):eaam8216. doi: 10.1126/scisignal.aam8216.

Kate L Henry ¹ ² , Debra Kellner ¹ , Bekim Bajrami ¹ , John E Anderson ¹ ² , Mercedes Beyna ¹ , Govinda Bhisetti ¹ , Tom Cameron ¹ , Andrew G Capacci ¹ , Andrea Bertolotti-Ciarlet ¹ , Jun Feng ¹ , Benbo Gao ¹ , Brian Hopkins ¹ , Tracy Jenkins ¹ , Kejie Li ¹ , Tricia May-Dracka ¹ , Paramasivam Murugan ¹ , Ru Wei ¹ , Weike Zeng ¹ , Norm Allaire ¹ , Alan Buckler ¹ , Christine Loh ¹ , Peter Juhasz ¹ , Brian Lucas ¹ , Katelin A Ennis ¹ , Elisabeth Vollman ¹ , Ellen Cahir-McFarland ¹ , Erik C Hett ³ , Michelle L Ols ¹

Affiliations

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.