The goal of studies proposed here is to understand the role of the role of RNA-binding protein, CRD-BP, in melanocyte biology. Microphtalmia-associated transcription factor (MITF) is a principal regulator of melanocyte development and a pivotal factor in the survival and growth of malignant melanomas. Therefore understanding the mechanisms controlling the expression and function of MITF is extremely important as it will identify key components for melanocyte development, and differentiation. Regulation of mRNA turnover emerged in recent years as a major mechanism controlling gene expression. mRNA decay rates are responsive to developmental and environmental signals and dictated by cis-acting elements within the mRNA and by trans-acting factors, such as miRNAs and RNA-binding proteins. We have shown that MITF mRNA is a novel melanocyte/melanoma-specific target of CRD-BP. We demonstrated that CRD-BP directly binds to the 3'-UTR of MITF mRNA and prevents the binding of miR-340 to its target sites resulting in stabilization of the MITF transcript that leads to induction of MITF expression and activities. CRD-BP is a multifunctional RNA-binding protein that recognizes the mRNAs of MITF, bTrCP1, Gli1, c-myc, IGF2, tau, and other genes. We identified CRD-BP as a novel target of b-catenin/Tcf, and c-myc transcription factors. Our preliminary data demonstrate that in response to b-catenin signaling, CRD-BP binds and stabilizes mRNAs of c-myc and bTrCP1. CRD-BP is essential for induction of c-myc and bTrCP1 by b-catenin signaling. Transcriptional upregulation of CRD-BP by b-catenin/Tcf may therefore contribute to pleiotropic effects of the Wnt signaling pathway and could provide the foundation for the hypothesis that CRD-BP might have a significant function in Wnt/b-catenin-dependent melanocyte development. In addition to the regulation by Wnt signaling, our preliminary results show that hypoxia also induces the expression of CRD-BP. Taking into consideration the physiologically hypoxic environment of the skin, this novel mode of regulation of expression and function of CRD-BP could play a significant role in melanocyte growth and development. We hypothesize that by influencing the stability of MITF and other mRNAs, CRD-BP is essential for normal melanocyte development. We propose to study the role of CRD-BP in melanocyte biology, and the mechanisms and significance of its regulation in melanocytes. Pursuant to these goals, the specific aims are: 1. To define the requirement for CRD-BP in the growth and differentiation of melanocytes. 2. To delineate the mechanism(s) of CRD-BP regulation by hypoxia. 3. To analyze the (patho)physiologic significance of CRD-BP regulation by hypoxia in melanocytes.
Given the importance of melanocytes, better understanding of their development and differentiation would enrich our knowledge about the natural safe-guard of UV irradiation. The goal of the studies proposed here is to understand the role of that RNA-binding protein CRD-BP in melanocyte biology, and the mechanisms and significance of its regulation in melanocytes. Our studies will also address a significant gap in our knowledge of how the environment controls mRNA turnover rates, and will clarify the role for hypoxia in regulation of mRNA stability in melanocytes.
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