[CDK8/19 in Stress Response in Mouse Embryonic Fibroblast Model]

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Context:

• Cyclin-dependent kinases 8 and 19 (CDK8/19) are transcriptional regulators within the Mediator complex.
• Previous research on CDK8/19 functions relied heavily on tumor cell lines, potentially yielding irrelevant results.
• Unique functions of CDK8 and its paralog CDK19 have remained largely unelucidated.

Purpose:

• To investigate the combined roles of CDK8 and CDK19 in a whole organism and primary cell cultures.
• To engineer a novel mouse model (Cdk8^(fl/fl)/Cdk19^(-/-)/Rosa26/Cre/ERT2) for inducible CDK8 knockout and constitutive CDK19 knockout.
• To analyze the effects of CDK8/19 inhibition and knockout in mouse embryonic fibroblasts (MEFs).

Summary:

• CDK8/19 inhibition induced significant cell death in MEFs, while knockout reduced proliferation rates.
• RNA sequencing identified alterations in Wnt signaling, cytokine response, and osteoclast differentiation pathways.
• Novel roles in cytoskeleton regulation, differentiation, cell adhesion, extracellular matrix formation, and mitochondrial biogenesis were uncovered.
• CDK8/19 mediate stress responses to DNA damage and serum stimulation, which were impaired in knockout MEFs.

Impact:

• This study provides the first comprehensive analysis of CDK8/19 functions in a physiological context using a novel mouse model.
• Findings challenge previous assumptions based on tumor cell line data and highlight the critical roles of CDK8/19 in fundamental cellular processes.
• The results offer new insights into the regulation of Wnt signaling, differentiation, and stress responses, with potential implications for understanding development and disease.