The Role of PHLPP in Colon Cancer

PHLPP 在结肠癌中的作用

• 批准号: 8244527
• 负责人: Tianyan Gao
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244527
• 关键词: Address; Agreement; Apoptosis; Automobile Driving; Binding; Biological Models; Cancer Center; Cancer Etiology; Cell Polarity; Cell Proliferation; Cells; Cellular biology; Cessation of life; Colon Carcinoma; Colorectal Cancer; Colorectal Neoplasms; Development; Diagnosis; Down-Regulation; Epithelial; Epithelial Cells; Failure; Family; Frequencies; Goals; Growth; Health; Homeostasis; Howard Temin Award; Human; Human Development; Incidence; Intercellular Junctions; Intestines; Isoenzymes; Knock-out; Knockout Mice; Light; Malignant Neoplasms; Mediating; Mentored Research Scientist Development Award; Molecular; Names; Non-Small-Cell Lung Carcinoma; Oncogenic; PH Domain; Pathway interactions; Pharmacology and Toxicology; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Play; Process; Protein Dephosphorylation; Protein Kinase; Protein Kinase C; Protein phosphatase; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Regulation; Research; Research Personnel; Role; Scheme; Signal Pathway; Signal Transduction; Specimen; Testing; Tumor Suppressor Proteins; Ubiquitin; United States; Up-Regulation; base; cancer cell; cancer therapy; cell growth; citrate carrier; design; falls; gastrointestinal epithelium; in vivo; insight; leucine-rich repeat protein; multicatalytic endopeptidase complex; novel; overexpression; prevent; professor; research study; tumor; tumor growth; tumor initiation; tumorigenesis

DESCRIPTION (provided by applicant): Colorectal cancer is the second leading cause of cancer-related deaths in the United States with 112,000 new cases diagnosed per year and approximately 52,000 deaths estimated in 2007. Dysregulation of Akt and protein kinase C (PKC) contributes to tumorigenesis by promoting cell proliferation and inhibiting apoptosis. The signaling activation process of Akt and PKC has been studied in great detail. However, little is known about how the signals are turned off once activated. Recently, we have identified a family of novel protein phosphatases, PHLPP (PH domain Leucine-rich-repeats Protein Phosphatase) that directly dephosphorylates Akt and PKC. However, the role of PHLPP in cancer has not been defined. In the preliminary studies, we found that loss of PHLPP expression occurs with high frequency in human colorectal cancer specimens. Furthermore, our studies have suggested that PHLPP plays a role in regulating cell polarity. In light of our findings, the central hypothesis driving this proposal is that PHLPP serves as a tumor suppressor by regulating cell polarity in addition to its ability of turning off the growth signaling activated by Akt and PKC. The long-term goal of our studies is to better understand the physiological role of PHLPP and its contribution to colon cancer development and progression in vivo. The Specific Aims are: Aim 1: To define the molecular mechanism of PHLPP downregulation. The goal of this aim is to investigate the potential mechanism leading to PHLPP downregulation in cancer. We will test the hypothesis that the expression level of PHLPP is controlled by the ubiquitin proteasome pathway in cells, and preventing PHLPP degradation leads to upregulation of the protein. Aim 2: To determine the role PHLPP in maintaining cell polarity. We hypothesize that PHLPP exerts its function as a tumor suppressor by regulating cell polarity and cell growth. The functional effect of PHLPP on establishing epithelial cell polarity will be determined. To elucidate the underlying mechanism, we will test the hypothesis that PHLPP is required for epithelial junction formation by modulating PKC activity via binding to the polarity protein Scribble. Aim 3: To delineate the role of PHLPP in tumorigenesis in vivo. The hypothesis driving this aim is that loss of PHLPP expression contributes to the initiation and progression of colorectal tumors. We will address the question whether there is an increase of tumor incidence when PHLPP is knocked out, both basally and in combination with other carcinogenic factors. Furthermore, we will assess the contribution of altered cell polarity in normal development of gut epithelium and tumor initiation using the knockout mice. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer-related deaths in the United States with 148,000 new cases diagnosed per year and approximately 50,000 deaths estimated in 2007 and, among many contributing factors, aberrant protein phosphorylation resulting from hyperactivation of oncogenic signaling mediated by protein kinases such as Akt and PKC, is a key cause of colorectal cancer. We recently identified a novel protein phosphatase PHLPP that directly dephosphorylates Akt and PKC and terminates the growth signals activated by these kinases. We propose to determine the functional importance of PHLPP as a tumor suppressor in colorectal cancer and the results from this study will provide significant insights into the development of potential cancer therapy using PHLPP as a novel target.

描述（由申请人提供）：结直肠癌是美国与癌症相关死亡的第二大主要原因，每年诊断为112,000例新病例，2007年估计约52,000例死亡。 AKT和PKC的信号激活过程已经详细研究。但是，关于一旦激活的信号如何关闭，知之甚少。最近，我们已经确定了一种新型蛋白质磷酸酶家族，PHLPP（pH结构域富含亮氨酸重复的蛋白质磷酸酶），该酶直接脱磷酸化Akt和PKC。但是，尚未定义PHLPP在癌症中的作用。在初步研究中，我们发现PHLPP表达的丧失在人类结直肠癌标本中高频出现。此外，我们的研究表明，PHLPP在调节细胞极性中起作用。鉴于我们的发现，推动该建议的中心假设是，除了关闭AKT和PKC激活的生长信号传导的能力外，PHLPP通过调节细胞极性来充当肿瘤抑制器。我们研究的长期目标是更好地了解PHLPP的生理作用及其对体内结肠癌发展和进展的贡献。具体目的是：目标1：定义PHLPP下调的分子机制。该目标的目的是研究导致癌症中PHLPP下调的潜在机制。我们将检验以下假设：PHLPP的表达水平受细胞中泛素蛋白酶体途径控制，并防止PHLPP降解会导致蛋白质的上调。目标2：确定PHLPP在维持细胞极性中的作用。我们假设PHLPP通过调节细胞极性和细胞生长来发挥其作为肿瘤抑制器的功能。将确定PHLPP对建立上皮细胞极性的功能效应。为了阐明潜在的机制，我们将通过通过与极性蛋白涂鸦的结合来调节PKC活性来测试上皮结形成所必需的假设。目标3：描绘PHLPP在体内肿瘤发生中的作用。推动该目标的假设是，PHLPP表达的丧失有助于结直肠肿瘤的起始和进展。我们将解决一个问题，当pHLPP被淘汰时，肿瘤发生率是否增加，无论是基本上还是与其他致癌因子结合使用。此外，我们将使用基因敲除小鼠评估细胞极性改变在肠道上皮和肿瘤起始的正常发育中的贡献。 PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer-related deaths in the United States with 148,000 new cases diagnosed per year and approximately 50,000 deaths estimated in 2007 and, among many contributing factors, aberrant protein phosphorylation resulting from hyperactivation of oncogenic signaling mediated by protein kinases such as Akt and PKC, is a key cause of colorectal cancer.我们最近确定了一种新型的蛋白质磷酸酶PHLPP，该蛋白质磷酸酶PHLPP直接脱磷酸化AKT和PKC并终止这些激酶激活的生长信号。我们建议确定PHLPP作为结直肠癌肿瘤抑制因子的功能重要性，这项研究的结果将为使用PHLPP作为新靶标的潜在癌症治疗的发展提供重要的见解。