Regulation of Stat3 by p53 in cancer Cells

癌细胞中 p53 对 Stat3 的调节

• 批准号: 6779707
• 负责人: Jiayuh Lin
• 金额: $ 1.16万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-09 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6779707
• 关键词: DNA binding protein; JAK kinase; angiogenesis; apoptosis; biological signal transduction; breast neoplasms; carcinogenesis; cell growth regulation; cell line; cell proliferation; clinical research; enzyme inhibitors; gel mobility shift assay; gene deletion mutation; genetic transcription; human tissue; mitogen activated protein kinase; neoplastic cell; neoplastic transformation; ovary neoplasms; p53 gene /protein; phosphorylation; prostate neoplasms; protein structure function; protein tyrosine phosphatase; vascular endothelial growth factors

In the proposed studies, we will examine the regulation of Stat3 (Signal transducer and activator of transcription 3) by p53 in breast and ovarian cancer cells expressing constitutively active Stat3. Constitutively active Stat3 may play a important role of oncogenic transformation of normal cells to malignant cells and may inhibit apoptosis. Recent studies suggest that constitutively Stat3 signaling contribute to oncogenesis by stimulating cell proliferation, promoting tumor angiogenesis, and preventing apoptosis. Constitutive activation of Stat3 has been frequently detected in a variety of cancer samples and cancer cell lines. These studies suggest that constitutively activated Stat3 plays a role on the human cancer carcinogenesis. Mutation of the p53 tumor suppressor is one of the most commonly detected genetic alterations in human cancer. Our preliminary studies demonstrated that expression of wild-type (wt) p53 but not mutant p53 significantly reduced phosphorylated or active form of Stat3 in breast, ovarian and prostate cancer cells that express constitutively active Stat3. Wt p53 also induced dramatic apoptosis in these cancer cell lines. We hypothesize that the anti-proliferative activities of wt p53 are not compatible with the constitutive activation of Stat3 in cancer cells. Constitutive activation of Stat3 by upstream activator(s) may activate p53 activities to induce growth arrest/apoptosis of cells. Activated p53 may induce a p53 downstream target that inhibits Stat3 in a negative feed back manner. p53 may then serve a safeguard against oncogenic deregulation of Stat3. Only cancer cells that further mutate p53 or inactivate p53 pathway may be able to escape p53-dependent apoptosis/growth arrest and be able to continue tumor progression. Therefore, constitutive activation of Stat3 may be selectively present in cancer cells that have harbored inactivating mutation or deletion of the p53 gene. This is a testable hypothesis and this hypothesis is partially supported by our survey from the published reports of the status of Stat3 and p53 in a panel of human cancer cell lines. We found that all breast, ovarian and prostate cancer cell lines that express constitutively active Stat3 only express mutant or null p53. In this proposal, we seek to examine the functional regulation of two potentially important genes that frequently altered in breast and ovarian cancers, Stat3 and p53. The following specific aims will be studied to address these questions: 1. Examine the molecular mechanism by which p53 inhibits Stat3 in cancer cells expressing constitutively active Stat3. 2. Examine whether the transcription activity of p53 is necessary to inhibit Stat3. 3. Evaluate whether down regulation of constitutively active Stat3 is associated with apoptosis induced by p53. 4. Examine whether constitutive activation of Stat3 selectively occurs in breast and ovarian cancer cell lines and cancer specimens containing p53 mutations or deletions.

在本研究中，我们将研究p53在表达组成型活性Stat3的乳腺癌和卵巢癌细胞中对Stat3（信号换能器和转录激活因子3）的调控。组成型活性Stat3可能在正常细胞向恶性细胞的致癌转化中发挥重要作用，并可能抑制细胞凋亡。最近的研究表明，组成型Stat3信号通过刺激细胞增殖、促进肿瘤血管生成和防止细胞凋亡来促进肿瘤的发生。Stat3的组成激活在各种癌症样本和癌细胞系中经常被检测到。这些研究表明，组成型激活Stat3在人类癌症的致癌过程中起着重要作用。p53肿瘤抑制基因突变是人类癌症中最常检测到的基因改变之一。我们的初步研究表明，野生型（wt） p53而非突变型p53的表达显著降低了表达组成型活性Stat3的乳腺癌、卵巢癌和前列腺癌细胞中Stat3的磷酸化或活性形式。在这些癌细胞系中，Wt p53也诱导了大量的细胞凋亡。我们假设wt p53的抗增殖活性与癌细胞中Stat3的组成性激活不相容。上游激活因子对Stat3的组成性激活可激活p53活性，从而诱导细胞生长停滞/凋亡。激活的p53可能诱导p53下游靶点以负反馈的方式抑制Stat3。p53可能会对Stat3的致癌调节起到保护作用。只有进一步突变p53或使p53通路失活的癌细胞才能逃脱p53依赖性的凋亡/生长停滞，并能够继续肿瘤进展。因此，Stat3的组成性激活可能选择性地存在于p53基因失活突变或缺失的癌细胞中。这是一个可验证的假设，我们对一组人类癌细胞系中Stat3和p53状态的公开报告的调查部分支持了这一假设。我们发现，所有表达组成型活性Stat3的乳腺癌、卵巢癌和前列腺癌细胞系只表达突变型或无效型p53。在这项提议中，我们试图检查Stat3和p53这两个在乳腺癌和卵巢癌中经常改变的潜在重要基因的功能调节。为解决这些问题，将研究以下具体目标：