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Cullin 4A (CUL4A) is an E3 ubiquitin ligase that directly affects DNA repair and cel cycle progression by targeting substrates including damage-specific DNA-binding protein 2 (DDB2), xeroderma pigmentosum complementation group C (XPC), chromatin licensing and DNA replication factor 1 (Cdt1), and p21. Recent work from our laboratory has shown that Cul4a-deficient mice have greatly reduced rates of ultraviolet-induced skin carcinomas. On a cel ular level, Cul4a-deficient cel s have great capacity for DNA repair and demonstrate a slow rate of proliferation due primarily to increased expression of DDB2 and p21, respectively. This suggests that CUL4A promotes tumorigenesis (as well as accumulation of skin damage and subsequent premature aging) by limiting DNA repair activity and expediting S phase entry. In addition, CUL4A has been found to be up-regulated via gene amplification or overexpression in breast cancers, hepatocellular carcinomas, squamous cell carcinomas, adrenocortical carcinomas, childhood medulloblastomas, and malignant pleural mesotheliomas. Because of its oncogenic activity in skin cancer and up-regulation in other malignancies, CUL4A has arisen as a potential candidate for targeted therapeutic approaches. In this review, we outline the established functions of CUL4A and discuss the E3 ligase’s emergence as a potential driver of tumorigenesis.
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Cell Signaling in Viral and Oncogenic Pathogenesis and Its Implications in Disease Diagnosis and Prognosis
Both viral diseases and cancer account for a large proportion of serious health problems.Viral infection and cancer are biologically and medically correlated and in many ways share common cellular pathways that lead to disease development or progression.Better understanding how these signaling events are specifically activated by different pathogenic stimuli and how they activate different downstream transcriptions in response to these stimuli at high specificity and efficiency will provide a new molecular basis for the development of novel disease biomarkers and therapeutic or preventive targets against both classes of diseases.Research in our laboratory has been prompted to investigate the regulation and modes of action of these pathways,with a more intensive focus on the NF-кB signaling,in the settings of severe or oncogenic viral infection as well as cancer development.It is hoped that our research will lead to eventual clinical application of biomarkers derived from these signaling pathways.