ROLE OF A NEW ETS FACTOR, PDEF, IN PROSTATE CANCER

新的 ETS 因素 PDEF 在前列腺癌中的作用

• 批准号: 6886322
• 负责人: TOWIA A. LIBERMANN
• 金额: $ 25.14万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6886322
• 关键词: androgen receptor; athymic mouse; enzyme activity; gel mobility shift assay; gene induction /repression; hormone related neoplasm /cancer; human tissue; male; mitogen activated protein kinase; neoplasm /cancer genetics; neoplastic process; neoplastic transformation; oncoproteins; prostate neoplasms; prostate specific antigen; transcription factor

DESCRIPTION: Prostate cancer has become the most common solid cancer in older men. Although androgen ablation therapy, surgery and radiation therapy are effective for the treatment of local prostate cancer, there is no effective treatment available for patients with metastatic androgen-independent disease. The poor prognosis for androgen-independent advanced prostate cancer reflects in part the lack of knowledge about the tumor's basic biology. In particular, very little is known about the molecular mechanisms that trigger the conversion of an initially androgen-dependent cancer to androgen-independence. Our goal is to understand the role of a novel prostate epithelium-specific transcription factor, PDEF (Prostate Derived Ets Factor), a member of the Ets transcription factor/oncogene family in human prostate cancer. PDEF is expressed in the luminal epithelial cells of normal human prostate and preliminary results indicate that PDEF expression is elevated in cancerous portions of the prostate. PDEF acts independently of androgen as a strong transcriptional enhancer of the PSA and PSMA promoter, two diagnostic markers used for monitoring androgen-dependent and -independent prostate cancer. Activated MAP kinases drastically enhance PDEF mediated transcriptional activation. PDEF also interacts and cooperates with the androgen receptor in inducing expression of the PSA gene. Thus, our hypothesis is that PDEF bypasses or activates the androgen receptor and thereby contributes to the progression from an initially androgen-dependent prostate cancer to an androgen-independent cancer. We propose to determine the role of this novel member of the Ets family in prostate cancer formation and progression and the possibility to use this new factor as another diagnostic tool and as a potential therapeutic target. Thus, the specific aims are: Specific Aim #1. Does PDEF play a crucial role in prostate cancer development or progression? Specific Aim #2. Is PDEF a critical regulator of prostate-specific PSA gene expression? Specific Aim #3. Can PDEF activity explain the conversion of prostate cancer cells to androgen-independence? Due to the importance of the Ets family in regulation of various tissue- and differentiation-specific genes and due to the direct implication of several members of the Ets family in various human cancers, PDEF is expected to play a role in prostate epithelial cell transformation or prostate cancer progression.

描述：前列腺癌已成为老年人最常见的实体癌。 男人。虽然雄激素消融治疗、手术和放射治疗 对于治疗局部前列腺癌有效，目前尚无有效方法 可用于转移性雄激素非依赖性疾病患者的治疗。 雄激素非依赖性晚期前列腺癌预后不良反映 这在一定程度上是因为缺乏对肿瘤基本生物学的了解。特别是， 人们对触发这种转化的分子机制知之甚少。 从最初的雄激素依赖型癌症到雄激素非依赖型癌症。我们的目标是 了解一种新的前列腺上皮特异性转录的作用 转录因子PDEF(前列腺源性ETS因子) 前列腺癌中的因子/癌基因家族。PDEF表示为 正常人前列腺腔上皮细胞及其初步结果 表明PDEF在卵巢癌组织中的表达升高。 前列腺。PDEF作为一种强大的转录因子独立于雄激素发挥作用 PSA和PSMA启动子的增强子，两个用于 监测雄激素依赖和非雄激素依赖性前列腺癌。激活的地图 蛋白水解酶能显著增强PDEF介导的转录激活。PDEF还 与雄激素受体相互作用和协同作用，诱导 PSA基因。因此，我们的假设是PDEF绕过或激活了 雄激素受体，从而促进从最初的 雄激素依赖型前列腺癌转变为雄激素非依赖型癌症。我们 建议确定ETS家族中这一新成员在 前列腺癌的形成和发展以及使用这种新技术的可能性 因子作为另一种诊断工具和潜在的治疗靶点。因此， 具体目标是： 具体目标1：PDEF在前列腺癌的发生中起关键作用吗？ 还是进步？ 特定目的#2：PDEF是前列腺特异性PSA基因的关键调节因子吗 表情？ 特定目标#3.PDEF活性能解释前列腺癌的转化吗 细胞对雄激素的非依赖性？由于ETS家族在中国的重要性 对各种组织和分化特异基因的调节，以及由于 ETS家族几个成员在不同人类中的直接意义 癌症，PDEF有望在前列腺上皮细胞中发挥作用 转化或前列腺癌进展。

项目成果

The receptor tyrosine kinase Axl is an essential regulator of prostate cancer proliferation and tumor growth and represents a new therapeutic target.

• DOI: 10.1038/onc.2012.89
• 发表时间: 2013-02-07
• 期刊: Oncogene
• 影响因子: 8

Proteomic identification of interleukin-2 therapy response in metastatic renal cell cancer.

转移性肾细胞癌中白细胞介素 2 治疗反应的蛋白质组学鉴定。

• DOI: 10.1016/j.juro.2007.09.016
• 发表时间: 2008
• 期刊: The Journal of urology
• 作者: Jones,Jon;Otu,HasanH;Grall,Franck;Spentzos,Dimitrios;Can,Handan;Aivado,Manuel;Belldegrun,ArieS;Pantuck,AllanJ;Libermann,TowiaA
• 通讯作者: Libermann,TowiaA

GADD45 proteins: central players in tumorigenesis.

• DOI: 10.2174/156652412800619978
• 发表时间: 2012-06
• 期刊: Current molecular medicine
• 影响因子: 2.5
• 作者: Tamura RE;de Vasconcellos JF;Sarkar D;Libermann TA;Fisher PB;Zerbini LF
• 通讯作者: Zerbini LF

Constitutive activation of nuclear factor kappaB p50/p65 and Fra-1 and JunD is essential for deregulated interleukin 6 expression in prostate cancer.

• 发表时间: 2003-05
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: L. Zerbini;Yihong Wang;Je-Yoel Cho;T. Libermann