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RP8

Michael Kracht: The role of CDK-NF-κB crosstalk in protein synthesis and secretion

AIM: Interleukin(IL)-1 is a key trigger of the NF-κB signaling pathway and initiates inflammatory diseases or cancer-associated inflammation. In the last period, we investigated the effects of different inhibitors of cyclin-dependent kinases (CDKs) which all suppressed survival and proliferation in tumor cells, on IL-1-NF-κB-mediated gene expression and secretion. Of note, some of the effects appeared to be independent of CDK inhibition, pointing to a non-canonical, IL-1-regulated pathway that maintains inflammatory mRNA expression and protein secretion. The aim of the renewal project is to decipher the molecular mechanisms of the non-canonical CDK pathways in IL-1-NF-κB-mediated inflammation using auxin-inducible degron models. Second, we will analyze the effects of a CDK12 PROTAC on the conventional / unconventional secretion pathways that establish the secretome and functionally investigate consequences for the TME using tumor cell macrophage co-cultures and precision-cut lung slices.

STATE of the ART: IL-1 strongly activates the NF-κB signaling pathway and NF-κB-mediated secretion, thereby contributing to the reprogramming of the inflammatory TME. Recent data suggest that the IL-1-NF-κB system and various CDKs crosstalk at several intracellular levels to control the expression and release of proteins. We and others demonstrated that CDK4 / 6 supported IL-1-NF-kappaB-dependent gene expression, while CDK12 (i) regulates specific sets of DNA damage response genes (ii) phosphorylates multiple substrates, and (iii) controls mRNA turnover and translation. These data suggest that several CDKs have additional functions in the entire gene expression pathway that reach beyond regulating cell cycle or transcriptional elongation. Elucidating the underlying mechanisms will (i) reveal the cooperativity of CDKs with the IL-1-NF-κB system in the regulation of genes, (ii) be beneficial in the understanding of cell-type-specific immunosuppressive side effects of CDK inhibitors, and (iii) uncover new modes of actions of CDKs for the regulation of secretomes.