The Role of PHLPP in Colon Cancer

PHLPP 在结肠癌中的作用

• 批准号: 8495058
• 负责人: Tianyan Gao
• 金额: $ 24.55万
• 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/8495058
• 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; 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; intestinal homeostasis; 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.

描述（由申请人提供）：结直肠癌是美国癌症相关死亡的第二大原因，每年诊断出 112,000 例新病例，2007 年估计约有 52,000 例死亡。Akt 和蛋白激酶 C (PKC) 的失调通过促进细胞增殖和抑制细胞凋亡来促进肿瘤发生。 Akt 和 PKC 的信号激活过程已被详细研究。然而，人们对信号一旦激活后如何关闭知之甚少。最近，我们鉴定了一个新型蛋白磷酸酶家族，PHLPP（PH 结构域富含亮氨酸重复蛋白磷酸酶），可直接使 Akt 和 PKC 去磷酸化。然而，PHLPP 在癌症中的作用尚未明确。在初步研究中，我们发现人类结直肠癌标本中 PHLPP 表达缺失的频率很高。此外，我们的研究表明 PHLPP 在调节细胞极性中发挥作用。根据我们的研究结果，推动这一提议的核心假设是，PHLPP 除了能够关闭 Akt 和 PKC 激活的生长信号传导之外，还可以通过调节细胞极性来充当肿瘤抑制因子。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生和进展的贡献。具体目标是： 目标 1：明确 PHLPP 下调的分子机制。该目的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，阻止 PHLPP 降解会导致该蛋白上调。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因子的功能。将确定 PHLPP 对建立上皮细胞极性的功能影响。为了阐明潜在的机制，我们将测试以下假设：PHLPP 通过与极性蛋白 Scribble 结合来调节 PKC 活性，是上皮连接形成所必需的。目标 3：描述 PHLPP 在体内肿瘤发生中的作用。推动这一目标的假设是 PHLPP 表达的丧失有助于结直肠肿瘤的发生和进展。我们将解决当 PHLPP 被基本敲除以及与其他致癌因素联合敲除时，肿瘤发病率是否会增加的问题。此外，我们将使用基因敲除小鼠评估细胞极性改变对肠上皮正常发育和肿瘤发生的贡献。