Mechanism of keratinocyte RXRalpha mediated melanoma skin cancer development

项目摘要 恶性黑色素瘤是美国增长最快的癌症之一， 目前仍有治疗方法。太阳紫外线（UV）辐射，尤其是儿童时期的阳光照射， 黑色素瘤重要病因危险因素。视黄酸X受体（RXR），核内 受体（NR）超家族，是转导多种细胞信号的中心协调者。背景下 在研究RXR在皮肤中的作用时，我们发现了一种意想不到的新作用， 黑色素瘤发生：RXR <$[ep-/-]小鼠，特别是在表皮角质形成细胞中缺乏RXR <$， 黑色素细胞生长（MG）类似黑色素瘤在高频率时，受到两步 化学致癌方案（DMBA+TPA）。我们的研究结果表明，RXR可能调节一种 角质形成细胞->黑素细胞信号传导途径参与黑素细胞增殖的控制。 因此，我们已经产生了一个新的小鼠模型的黑色素瘤。然而，分子 RXR这些活性的基础机制尚不清楚。鉴于角质细胞的重要性 在调节黑素细胞有丝分裂中，了解这种调节在黑色素瘤中如何变得异常， 是重要的，因为它可能导致发展有效的治疗策略，以抵消 黑色素瘤形成和进展。我们的长期目标是确定信号的机制 角质形成细胞和黑素细胞之间的转导，有助于黑色素瘤的发展。 根据上述观察和初步数据，我们提出以下两个具体建议： 目标。首先，我们建议阐明角质形成细胞的细胞和分子机制， 控制黑素细胞有丝分裂和转化，导致恶性表型。我们的工作 假设RXR直接或间接抑制内皮素1（ET-1）的角质形成细胞表达， SCF、POMC和FGF 2可能以旁分泌方式调节黑素细胞的有丝分裂。 第二，我们建议确定控制黑素细胞的细胞内靶点（黑素细胞因子 稳态和UV诱导的黑色素瘤形成。我们的假设是黑素细胞因子， 如细胞周期蛋白依赖性激酶-4（Cdk 4），可能调节这些细胞对细胞周期蛋白的反应性。 角化细胞衍生的旁分泌因子的促有丝分裂作用。我们认为，我们在这方面的努力 本文所述的工作将导致对机制的详细理解 黑色素细胞有丝分裂和黑色素瘤的发生受角质形成细胞RXR调节，也许其他 旁分泌因子拟议的项目具有潜在的创新性，因为我们的实验室生成了RXR。 [ep-/-]小鼠，其已用于这些研究，并且是第一个表征 RXR在表皮稳态过程中的皮肤。这一贡献是重大的，成果是预期的 对人类健康产生积极的影响，因为这项工作的结果将提供分子 未来药理学策略发展的基石， 治愈恶性黑色素瘤。

Project Summary Malignant melanoma is one of the fastest increasing cancer in the United States and no curative treatment is yet available. Solar ultraviolet (UV) radiation, especially childhood sun exposure is an important etiological risk factor of melanoma. Retinoid X Receptor ¿ (RXR¿), a member of the nuclear receptor (NR) superfamily, is a central coordinator for transducing diverse cellular signals. In the context of studying the role of RXR¿ in skin, we have discovered an unexpected and novel role for this NR in melanomagenesis: RXR¿[ep-/-] mice, specifically lacking RXR¿ in epidermal keratinocytes, develop melanocytic growths (MGs) resembling melanoma at high frequency when subjected to a two-step chemical carcinogenesis protocol (DMBA+TPA). Our results suggest that RXR¿ may regulate a keratinocyte-> melanocyte signaling pathway(s) implicated in the control of melanocytic proliferation. Thus, we have generated a new mouse model for melanomagenesis. However, the molecular mechanisms that underlie these activities of RXR are not known. Given the importance of keratinocytes in regulating melanocyte mitogenesis, understanding how this regulation becomes aberrant in melanoma is significant, since it can possibly lead to the development effective therapeutic strategies to counteract melanoma formation and progression. Our long-term goal is to identify the mechanisms of signal transduction between keratinocytes and melanocytes that contribute to the development of melanoma. Based on the above observations and from the preliminary data, we propose the following two Specific Aims. First, we propose to elucidate the cellular and molecular mechanisms by which keratinocytes control melanocyte mitogenesis and transformation leading to a malignant phenotype. Our working hypothesis is that RXR¿, directly or indirectly, represses keratinocytic expression of endothelin 1 (ET-1), SCF, POMC and FGF2 which may serve to regulate melanocytic mitogenesis in a paracrine manner. Second, we propose to identify intracellular targets (melanocytic factors) that control melanocyte homeostasis and UV-induced melanomagenesis. Our working hypothesis is that melanocytic factors, such as cyclin dependent kinase -4 (Cdk4), may modulate the responsiveness of these cells to the mitogenic effects of keratinocyte-derived paracrine factors. We believe that our efforts in the context of the work described herein will lead to a detailed understanding of the mechanism(s) by which melanocyte mitogenesis and melanomagenesis are regulated by keratinocytic RXR¿, and perhaps other paracrine factors. The proposed project is potentially innovative as our laboratory generated the RXR¿ [ep-/-] mouse that has been used for these studies, and was the first to characterize the in vivo role of RXR¿ in skin during epidermal homeostasis. This contribution is significant and the results are expected to have a positive impact on human health, because the outcome of the work will provide the molecular cornerstone for the development of future pharmacological strategies designed to treat, and ultimately cure malignant melanoma.