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中最常见的实体癌症 男人。尽管雄激素消融疗法、手术和放射疗法 对于局部前列腺癌的治疗有效，目前尚无有效的治疗方法 适用于患有转移性雄激素非依赖性疾病的患者的治疗。 雄激素非依赖性晚期前列腺癌的不良预后反映了 部分原因是缺乏对肿瘤基础生物学的了解。尤其， 关于触发转化的分子机制知之甚少 最初依赖雄激素的癌症转变为不依赖雄激素的癌症。我们的目标是 了解新型前列腺上皮特异性转录的作用 因子，PDEF（前列腺衍生的 Ets 因子），Ets 转录的成员 人类前列腺癌的因子/癌基因家族。 PDEF 的表达形式为 正常人前列腺管腔上皮细胞及初步结果 表明 PDEF 表达在癌变部分升高 前列腺。 PDEF 独立于雄激素发挥作用，作为一种强转录因子 PSA 和 PSMA 启动子的增强子，这两个诊断标记用于 监测雄激素依赖性和非依赖性前列腺癌。激活的地图 激酶显着增强 PDEF 介导的转录激活。 PDEF 也 与雄激素受体相互作用并协同诱导雄激素受体的表达 PSA基因。因此，我们的假设是 PDEF 绕过或激活 雄激素受体，从而有助于从最初的进展 雄激素依赖性前列腺癌转变为雄激素非依赖性癌症。我们 提议确定 Ets 家族的这位新成员在 前列腺癌的形成和进展以及使用这种新方法的可能性 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 在前列腺癌的发展中起着至关重要的作用吗 或进展？ 具体目标#2。 PDEF 是前列腺特异性 PSA 基因的关键调节因子吗 表达？ 具体目标#3。 PDEF活性可以解释前列腺癌的转变吗 细胞不依赖雄激素？由于 Ets 家族在 各种组织和分化特异性基因的调节，并且由于 Ets家族的几个成员对各种人类的直接影响 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