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; 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.

在拟议的研究中，我们将通过p53在表达组成性活性STAT3的乳腺癌和卵巢癌细胞中检验p53对STAT3的调节（转录信号和转录3）的调节。 组成性活性STAT3可能起着正常细胞向恶性细胞致癌转化的重要作用，并可能抑制凋亡。 最近的研究表明，组成性STAT3信号传导通过刺激细胞增殖，促进肿瘤血管生成和预防凋亡而导致肿瘤发生。 在多种癌症样品和癌细胞系中经常检测到STAT3的组成型激活。 这些研究表明，组成型激活的STAT3对人类癌症的发生作用。 p53肿瘤抑制剂的突变是人类癌症中最常见的遗传改变之一。 我们的初步研究表明，野生型（WT）p53但没有突变体p53的表达显着降低了乳腺癌，卵巢和前列腺癌细胞中STAT3的磷酸化或活性形式，以表达组成性活性STAT3。 WT p53还诱导了这些癌细胞系中的急剧凋亡。 我们假设WT p53的抗增殖活性与癌细胞中STAT3的本构激活不兼容。上游激活剂对STAT3的组成型激活可能会激活p53活性以诱导细胞的生长停滞/凋亡。 活化的p53可能会诱导下游靶标，该目标以负反馈方式抑制STAT3。 然后，p53可以防止STAT3的肿瘤过失管制。 只有进一步突变p53或灭活p53途径的癌细胞才能逃脱依赖p53的凋亡/生长停滞，并能够继续肿瘤进展。 因此，STAT3的组成型激活可以选择性地存在于已有p53基因的突变或缺失的癌细胞中。 这是一个可检验的假设，我们的调查在人类癌细胞系中已发表的STAT3和p53状态的报告得到了我们的调查，部分支持了这一假设。 我们发现，所有表达组成性STAT3的乳腺，卵巢和前列腺癌细胞系仅表达突变体或无效p53。 在此提案中，我们试图检查两个潜在重要基因的功能调节，这些基因经常在乳腺癌和卵巢癌中改变，即STAT3和P53。将研究以下具体目标以解决以下问题： 1。检查p53在表达组成活性STAT3的癌细胞中抑制STAT3的分子机制。 2。检查p53的转录活性是否需要抑制STAT3。 3。评估组成性活性STAT3的下调是否与p53诱导的凋亡有关。 4。检查STAT3的本构激活是否在乳腺癌和卵巢癌细胞系以及含有p53突变或缺失的癌症标本中发生。