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  • br NF B and STAT as Regulators of the CDK

    2021-07-26


    NF-κB and STAT as Regulators of the CDK System While current data support the concept that CDKs augment the proinflammatory activity of NF-κB, our understanding of the function of this transcription factor system in CDK regulation remains patchy. Seminal studies showed the contribution of NF-κB to the expression of CDK regulatory proteins such as cyclin D1 26, 27, 63. Inhibition of NF-κB by expression of a non-degradable IκB (inhibitor of NF-κB) mutant resulted in impaired flumethasone progression. This defect could be rescued by ectopic expression of cyclin D1, showing its relevance for NF-κB-dependent cell cycle progression [64]. In addition, transcription of the CDKN1A gene is upregulated by NF-κB and STAT transcription factors. The list of NF-κB target genes also includes CDK4 and CDK6, which are transcriptionally induced by the NF-κB2 (p52) subunit [65]. The NF-κB system also employs further mechanisms to control CDKs and their regulators. The NF-κB activating kinase IKKα (IκB kinase α) phosphorylates cyclin D1 and p27KIP1, thus affecting the subcellular distribution and function of the modified proteins [66]. The general role of NF-κB in the regulation of cell proliferation strongly depends on the organ and tissue type, as revealed by a variety of different mouse models. Mice lacking the transcriptional activation domain of the NF-κB c-REL (v-Rel avian reticuloendotheliosis viral oncogene homolog) protein show an enlarged spleen due to lymphoid hyperplasia, suggesting an anti-proliferative role for this transcription factor [67]. The same mice also display bone marrow hypoplasia, providing evidence for a pro-proliferative function. It is also important to note that the effects of NF-κB on cell proliferation are in part due to indirect effects. For example, the inhibition of NF-κB by overexpression of IκB or deletion of IKKβ in basal layer keratinocytes leads to their hyperproliferation [68]. Importantly, keratinocyte hyperproliferation in these models can be induced by immune infiltrates containing cytokines. Because the hyperproliferative phenotype can be reversed by deleting the TNF receptor [69], these effects are cytokine-driven and do not represent an intrinsic feature of keratinocytes.
    Aberrant CDK Signaling in Tumor-Promoting Inflammation The systematic analysis of cancer genomes has revealed that genes encoding D-type cyclins and inhibitors of CDKs are frequently mutated in cancer [70]. Many cancers show increased CDK4 and CDK6 activities, or the occurrence of point mutations such as the CDK4 (Arg24Cys) mutation which allows escape from INK4 inhibition [71]. These genomic alterations typically lead to increased CDK activities, with a preference of CDK6 to be active in mesenchymal tumors and CDK4 in epithelial malignancies 6, 20. In contrast to nontransformed cells, many human tumor cell lines become addicted to augmented CDK activity during the neoplastic process 70, 72, 73, 74. Mutations in CDKs and their regulators alone are typically not sufficient for cell transformation, which requires further mutations. Mouse models have revealed that these additional mutations determine the relative contribution of the CDK system. For example, breast cancer driven by ERBB2 (Erb-B2 receptor tyrosine kinase 2) and HRAS (Harvey rat sarcoma viral oncogene homolog) is prevented by knockout of cyclin D1 and hence CDK4 activity, while MYC (v-Myc avian myelocytomatosis viral oncogene homolog)- or WNT1 (Wingless-Type MMTV Integration Site Family, Member 1)-driven oncogenic pathways are independent of cyclin D1 [75]. CDK inhibitors do not only target the cell proliferation machinery, but they can also inhibit tumor-promoting inflammation. The vast majority of all cancers are caused by somatic mutations and environmental factors such as inflammation 76, 77, 78. Inflammatory conditions occur before a malignant change or they can be induced as a consequence of an oncogenic change [79]. Many tumors benefit from mediators of inflammation which can be released directly by tumor cells or by cells residing in their microenvironment. In such a situation, a cocktail of active factors including growth and survival factors, proangiogenic effectors, and even extracellular matrix-modifying enzymes facilitate angiogenesis, invasion, and metastasis [80]. The pathophysiological relevance of these processes explains that the prevention or treatment of inflammation-driven cancers benefits from adjuvant therapy with anti-inflammatory drugs [81]. The inhibition of proinflammatory CDKs will thus be a desired side-effect in cancer therapy, but may also be of importance in the treatment of inflammatory diseases.