Regulation of the tumor suppressor PTEN

描述（由申请方提供）：恶性转化和肿瘤进展通常伴随着具有抗肿瘤活性的基因的丢失。其中一种肿瘤抑制基因PTEN位于10号染色体q22-23处，几乎一半的子宫内膜癌、三分之一的胶质母细胞瘤和广泛的其他人类肿瘤（如前列腺癌、脑癌、乳腺癌、肾癌和白血病）中的该位点发生改变。此外，PTEN在三种人类遗传性癌症易感综合征中发生突变。因此，PTEN似乎在一个途径中发挥重要作用，该途径的缺失使细胞对恶性转化敏感。最近已经清楚，PTEN蛋白是一种特异性磷脂酰肌醇3-磷酸酶（PI 3 K），其直接抵消磷脂酰肌醇3-激酶（PI 3 K）在细胞生长、存活、运动、细胞骨架结构和分化中的多方面作用。目前对PTEN的调控知之甚少。这项资助将解决一个新的假说，调节PTEN的生物学功能。具体目标1（PTEN的转录调节）代表了我们最近发现的继续，即PTEN基因的转录受Egr-1转录因子的调节。Egr-1也是一种肿瘤抑制因子，并介导响应于UV和g-照射和其他促凋亡刺激的PTEN上调。我们的工作将解决我们的假设，即PTEN转录受D3-磷酸肌醇（PTEN的底物）的影响，作为反馈回路的一部分，可能包括Egr-1和/或其他Egr家族成员，特别是在淋巴细胞和肿瘤中。将解决肿瘤中存在的情况。 具体目标2（PTEN的翻译后调节）将探索用于调节PTEN降解的类似模型。我们的假设预测，D3-磷酸肌醇影响营业额的PTEN的机制，涉及磷酸化在S380（加上相邻的网站），保护蛋白质降解。我们将研究这一机制，确定负责激酶（很可能是PKB），和蛋白水解的途径。我们还将评估S380磷酸化对PTEN功能其他方面的影响。总之，我们的研究结果有望提高我们对PTEN参与致癌作用的分子机制的理解，并可能为合理的药物设计开辟新的途径。程序性细胞死亡的两个途径（PTEN和Egr-1）之间可能的串扰可能与理解和最终治疗大量人类癌症高度相关。

DESCRIPTION (provided by applicant): Malignant transformation and tumor progression are frequently accompanied by the loss of genes with antitumor activity. One such tumor suppressor gene, PTEN, is located on chromosome 10 at q22-23, a locus that is altered in almost half of all endometrial cancers, in a third of glioblastomas, and in a wide range of other human neoplasms, such as prostate, brain, breast, kidney cancers, and leukemias. In addition, PTEN is mutated in three human inherited cancer-predisposing syndromes. Thus, PTEN appears to play an important role in a pathway the loss of which sensitizes cells to malignant transformation. It has recently become clear that the PTEN protein is a specific phosphatidylinositol 3-phosphatase (PI3Pase) that directly counteracts the versatile effects of phosphatidylinositol 3-kinase (PI3K) in cell growth, survival, motility, cytoskeletal architecture and differentiation. The regulation of PTEN is currently poorly known. This grant will address a novel hypothesis for the regulation of the biological function of PTEN. Specific aim 1 (Transcriptional regulation of PTEN) represents the continuation of our recent finding that the transcription of the PTEN gene is regulated by the Egr-1 transcription factor. Egr-1 is also a tumor suppressor and mediates the upregulation of PTEN in response to UV and g-irradiation and other proapoptotic stimuli. Our work will address our hypothesis that PTEN transcription is influenced by D3-phosphoinositides (the substrates for PTEN) as part of a feedback loop that may include Egr-1 and/or other Egr family members, particularly in lymphoid cells and tumors. The scenarios present in tumors will be addressed. Specific aim 2 (Post-translational regulation of PTEN) will explore a similar model for the regulation of PTEN degradation. Our hypothesis predicts that D3-phosphoinositides influence the turnover of PTEN by a mechanism that involves phosphorylation at S380 (plus adjacent sites), which protects the protein from degradation. We will study this mechanism, identify the responsible kinase (could well be PKB), and the route of proteolysis. We will also evaluate the effects of S380 phosphorylation on other aspects of PTEN function. Taken together, our results are expected to improve our understanding of the molecular mechanisms by which PTEN participates in carcinogenesis and may open new avenues for rational drug design. The possible crosstalk between two pathways of programmed cell death (PTEN and Egr-1) may be highly relevant for the understanding and eventual treatment of a large number of human cancers.