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  • Investigations of mice lacking up to three CDKs identified t

    2020-10-23

    Investigations of mice lacking up to three CDKs identified the mitosis-regulating kinase CDK1 as the main essential component for the cell cycle, whereas ablation of other Triflurdine regulators such as CDK2, CDK4, or CDK6 did not result in defective proliferation 12, 13. Mouse models and specific CDK inhibitors have revealed the involvement of CDKs in many different biological processes ranging from hematopoiesis, apoptosis, and senescence to DNA repair [6]. These results show that the CDK system has a broad role in multiple functions beyond the cell cycle. Accordingly, phosphoproteomic studies allowed the identification of hundreds of new CDK phosphorylation substrates 14, 15, 16, 17, 18, 19. In addition, cyclins also regulate the response to several extra- and intracellular cues such as gene expression and differentiation [20]. These studies point to multiple cell cycle-independent emerging functions of CDKs, cyclins, and CDK inhibitor proteins that may be executed as monomeric proteins, by binding to new interaction partners, or through the new CDK substrate proteins (Figure 1B, lower left panel). In recent years biochemical, genetic, and pharmacological evidence has accumulated showing that both established and emerging functions of CDKs also contribute to the process of inflammation (Figure 1B, lower right panel). This occurs not only in proliferating cells but also in terminally differentiated cells of the immune system. The molecular mechanisms underlying the proinflammatory function of CDKs and of further proteins regulating their activities, such as INK4, p21CIP1, and p16INK4A, are only now beginning to emerge. We summarize these new results and also discuss the potential use of CDK inhibitors for the treatment of chronic and tumor-promoting inflammation.
    Inflammation Inflammation is triggered by harmful situations such as pathogen invasion or cell damage. These events are accompanied by exposure of pathogen-associated molecular patterns (PAMPs) or danger (or damage)-associated molecular patterns (DAMPs), which are sensed by pattern recognition receptors (PRRs) [21]. These activated receptors rapidly induce signaling cascades that result in the activation of proinflammatory transcription factors such as NF-κB (nuclear factor κB), AP-1 (activator protein 1) and STAT3 (signal transducer and activator of transcription 3) (Box 1). The activated transcription factors lead to production of inflammatory mediators such as prostaglandins, reactive oxygen intermediates, cytokines (interleukins; e.g., IL-1, IL-6, IL-33), tumor necrosis factor (TNF) and chemokines (e.g., IL-8, CXCL1-3, CCL20, CCL2). In principle, cytokines can be produced by all nucleated cells in response to initial signals from PAMP or DAMP receptors [22]. Binding of inflammatory mediators to their own receptors helps to potently amplify the innate immune reaction to mount a powerful response [23]. The coordinated release of cytokines regulates processes such as host immune cell activation, migration of white blood cells, wound healing and blood vessel formation. The levels of inflammatory genes must be tightly controlled because their unwanted expression in the absence of PAMP or DAMP signals may cause chronic inflammatory diseases such as rheumatoid arthritis (RA). These diseases are characterized by permanently elevated levels of cytokines such as TNF and IL-1 [24]. By contrast, insufficient inducible cytokine expression can preclude the successful clearance of the infection or inflammatory cell debris. The maintenance of this delicate balance is achieved by many coregulators and cofactors that control the activity of proinflammatory transcription factors [25]. While it is well known that NF-κB regulates the expression of components of the CDK/cyclin system 26, 27, recent results show that also these cell cycle regulators directly shape proinflammatory gene expression. The molecular mechanisms underlying these proinflammatory functions are now emerging and may open new therapeutic opportunities for the treatment inflammatory or proliferative diseases.