ABSTRACT
Cullin 4A (CUL4A) is an E3 ubiquitin ligase that directly affects DNA repair and cell 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 cellular level, Cul4a-deficient cells 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.
Subject(s)
Animals , Humans , Carcinogenesis , Metabolism , Cell Cycle , Cell Proliferation , Cullin Proteins , Genetics , Metabolism , DNA Damage , DNA Repair , DNA-Binding Proteins , Metabolism , Drug Delivery Systems , Neoplasms , Genetics , Metabolism , Proto-Oncogene Proteins p21(ras) , Metabolism , Skin Neoplasms , Genetics , Metabolism , PathologyABSTRACT
Congenital cataract is the leading cause for low vision and blindness in infancy and childhood.One third of congenital cataract cases are associated with genetic mutation and hereditary,and the etiology of congenital cataract is heterogenous and its phenotype is variable.The known mutation genes include encoding structural lens protein,gap junction protein,membrane protein and lens-developing-related regulatory protein.Location and identification of mutation genes in congenital cataract patients are necessary for us to understand the molecular defects and pathophysiologic features of congenital cataract.With the development of molecular biology techniques,the study on the mechanism of congenital cataract has made great progress,which is helpful for us to further understand the heredity pattern as well as the influence of environment and nourishment to the metabolism of lens.The purpose of this review was to summarize the literature of current advance in the study on molecular genetic basis of congenital cataract.