The role of RB in the retina & other tissues

视网膜母细胞瘤蛋白(Rb)是抑制肿瘤、调节细胞增殖和抑制肿瘤生长的关键蛋白。 视网膜、视网膜色素上皮、晶状体等眼组织中的细胞死亡。我们的长期目标是 研究是为了了解RB在眼睛健康和疾病中的重要性，这可能会让我们发展 治疗眼疾的新疗法。Rb通过与E2F相互作用定位于基因启动子 转录因子，它通过组装多聚染色质重塑来调节基因表达 复合体。Rb本身受两个关键的磷酸化事件调节：C末端的磷酸化 阻断Rb抑制细胞增殖的能力，而Rb丝氨酸-567处的额外磷酸化 阻断RB抑制细胞死亡的能力。同时，我们已经证明了RB对于 眼黑素细胞的分化和存活--一种在青光眼中起重要作用的色素细胞 眼部黑色素瘤、白化病、小眼炎等眼科疾病的发病机制。当RB最小时 被磷酸化后，它处于最活跃的形式，并能够与小眼球转录协同作用 因子(MITF)诱导黑素细胞分化和停止增殖。当RB变得部分 被磷酸化后，它失去了抑制细胞增殖的能力，但仍然阻止了细胞死亡。当RB为 丝氨酸-567的磷酸化使其完全失活，不再能防止细胞死亡。适当地， 丝氨酸-567的磷酸化只发生在异常细胞中。我们假设，对 Rb根据其磷酸化状态对细胞增殖和细胞死亡起到缓冲作用 在正常细胞增殖过程中的无意细胞死亡，同时提供了一种消除异常的机制 可能导致癌症和其他疾病的细胞。利用我们的眼部黑素细胞模型，我们提出了一系列 围绕三个特定目标组织的实验，以确定RB如何调控细胞增殖， 眼黑素细胞的分化和细胞死亡。了解RB如何完成这些功能 可能导致新的治疗方法来消除癌细胞，或者，防止正常细胞的损失 并促进黄斑变性和视网膜色素变性等眼部疾病的组织再生。 因此，这些目标与NEI的愿景声明高度相关，它们涉及几个 视网膜疾病计划的主要计划目标和目标。

The retinoblastoma protein (Rb) is critical for suppressing cancer, regulating cell proliferation, and inhibiting cell death in the retina, retinal pigment epithelium, lens and other ocular tissues. The long-term goal of our research is to understand the importance of Rb in ocular health and disease, which may allow us to develop new therapies for eye disorders. Rb localizes to gene promoters through its interaction with E2F transcription factors, and it regulates gene expression by assembling multimeric chromatin remodeling complexes. Rb itself is regulated by two key phosphorylation events: phosphorylation of the C-terminus blocks the ability of Rb to inhibit cell proliferation, whereas additional phosphorylation of Rb at serine-567 blocks the ability of Rb to inhibit cell death. Concurrently, we have shown that Rb is critical for the differentiation and survival of ocular melanocytes - a type of pigment cell that plays an important role inthe pathogenesis of ocular melanoma, albinism, microphthalmia and other eye diseases. When Rb is minimally phosphorylated, it is in its most active form and is able to cooperate with the microphthalmia transcription factor (MITF) to induce melanocytes to differentiate and cease proliferating. When Rb becomes partially phosphorylated, it looses the ability to inhibit cell proliferation but it still blocks cell death. When Rb is completely inactivated by phosphorylation of serine-567, it can no longer prevent cell death. Appropriately, serine-567 phosphorylation occurs only in abnormal cells. We hypothesize that the separate regulation of cell proliferation and cell death by Rb according to its phosphorylation state serves as a buffer against inadvertent cell death during normal cell proliferation while providing a mechanism for eliminating abnormal cells that could lead to cancer and other diseases. Using our ocular melanocyte model, we propose a series of experiments organized around three specific aims to determine how Rb regulates cell proliferation, differentiation and cell death in ocular melanocytes. Understanding how Rb accomplishes these functions could result in new treatments to eliminate cancer cells and alternatively, to prevent the loss of normal cells and encourage tissue regeneration in eye diseases such as macular degeneration and retinitis pigmentosa. Consequently, these aims are highly relevant to the vision statement of the NEI, and they address several major program goals and objectives of the Retinal Diseases Program.