CSF1 AND CSF1R AND BREAST AND OVARIAN CARCINOMA

描述：（改编自研究者摘要）基于他们的 他们在最后一次更新资金期间观察到， 几种卵巢癌细胞系和肿瘤标本 表达缺少外显子2的CSF-1 R转录物，外显子2含有翻译 全长蛋白质起始位点和两个不同的磷酸酪氨酸 CSF-1 R的残基似乎与蛋白酶相关， 生产、侵入性或转磷酸化其他 受体。 他们还获得证据表明，迄今为止， 未知的蛋白质结合到CSF-1 R的周围序列， 包括TYR-723，当后者被磷酸化时。 在当前的申请中，他们建议进一步调查这些问题 观察并确定1）由剪接编码的蛋白质是否 变异卵巢癌CSF-1 R转录本，并定义其如何 生物化学和生理功能与野生型相关 CSF-1 R蛋白，特别是关于组成性自磷酸化 对TYR和细胞转化的影响 CSF-1的来源; 2）这些CSF-1 R转录物的表达和 它们在体内编码的N-末端截短的蛋白质在良性和 肿瘤性卵巢上皮细胞; 3）是否药物或遗传变化 其阻断Y 723远端的信号转导，模拟Y->F突变， 定位并显著减少（如果不是消除）CSF-1 R对乳腺癌的刺激 上皮细胞非贴壁依赖性生长和致瘤性; 4）是否 产生针对我们的肽的单克隆抗体， 将该位点酪氨酸磷酸化的CSF-1 R与其他位点区分开来 配体活化的酪氨酸激酶，如EGF-R、HER-2/neu和c-met。

DESCRIPTION: (adapted from the investigator's abstract) Based on their observations made during their last period of renewal funding, they observe that several ovarian carcinoma derived cell lines and tumor specimens express a CSF-1R transcript lacking exon 2 which contains the translation start site for the full-length protein and that two distinct phosphotyrosine residues of the CSF-1R appear to be correlated either with protease production, invasiveness or the ability to transphosphorylate other receptors. They also have obtained evidence that a small 60 kda heretofore unknown protein binds to the CSF-1R at the sequence surrounding and including TYR-723 when the latter is phosphorylated. In their current application, they propose to further investigate these observations and determine 1) whether the protein encoded by the splice variant ovarian carcinoma CSF-1R transcripts and define how their biochemical and physiological functions relate to those of the wild-type CSF-1R protein, specifically with regard to constitutive autophosphorylation on TYR and cell transformation in the absence of exogenous or autocrine sources of CSF-1; 2) whether the expression of these CSF-1R transcripts and the N-terminally truncated proteins they encode in vivo in benign and neoplastic ovarian epithelial cells; 3) whether agents or genetic changes which block signal transduction distal to Y723 mimic Y-->F mutations at that site and markedly diminish (if not abolish) CSF-1R stimulation of mammary epithelial cell anchorage-independent growth and tumorigenicity; 4) whether to produce monoclonal antibodies to our peptide surrounding Y809 able to discriminate CSF-1R phosphorylated on tyrosine at this site from other ligand-activated tyrosine kinases such as EGF-R, HER-2/neu, and c-met.