2. Academic Validation
  3. CDK12-mediated transcriptional regulation of noncanonical NF-κB components is essential for signaling

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

Affiliations

  • 1 Biogen, 225 Binney Street, Cambridge, MA 02142, USA.
  • 2 Department of Pharmacology, Boston University School of Medicine, Boston, MA 02118, USA.
  • 3 Biogen, 225 Binney Street, Cambridge, MA 02142, USA. erikhett@gmail.com.
PMID: 30065029 DOI: 10.1126/scisignal.aam8216
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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