Expression of a phosphorylated substrate domain of p130Cas promotes PyMT-induced c-Src-dependent murine breast cancer progression.
Expression of a phosphorylated substrate domain of p130Cas promotes PyMT-induced c-Src-dependent murine breast cancer progression.
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p130Cas 磷酸化底物结构域的表达促进 PyMT 诱导的 c-Src 依赖性小鼠乳腺癌进展。
DOI：
10.1093/carcin/bgt238
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发表时间：
2013
期刊：
影响因子：
4.7
通讯作者：
Kirsch,KathrinH
中科院分区：
文献类型：
--
作者：
Zhao,Yingshe;Kumbrink,Joerg;Lin,Bor-Tyh;Bouton,AmyH;Yang,Shi;Toselli,PaulA;Kirsch,KathrinH
p130 Cas（Crk相关底物）/BCAR 1（乳腺癌抗雌激素抵抗1）在人乳腺肿瘤中的高表达是预后不良和总生存率不良的标志。p130 Cas是酪氨酸激酶c-Src的下游靶点。p130 Cas通过其磷酸化底物结构域（SD）介导的信号传导以及与效应分子的相互作用直接促进肿瘤进展。我们以前开发了一种组成型磷酸化的p130 Cas SD分子Src*/SD（以前称为Src*/CasSD），它可以作为诱饵分子，减弱v-crk转化的鼠成纤维细胞和人乳腺癌细胞中的转化表型。为了验证该分子在体内的功能，我们建立了小鼠乳腺肿瘤病毒（MMTV）-长末端重复序列-Src */SD转基因小鼠，分析了乳腺发育和肿瘤形成。Src*/SD分子在MMT长末端重复序列启动子下的转基因表达不干扰正常乳腺发育或诱导小鼠肿瘤，观察时间长达11个月。为了评估Src*/SD分子对体内肿瘤发展的影响，我们利用依赖于c-Src的MMT-多瘤中T抗原（PyMT）小鼠乳腺癌模型。与Src*/SD小鼠杂交的PyMT小鼠显示出加速的肿瘤形成。肿瘤的早期发作可以通过Src* 结构域与PyMT的相互作用以及将融合的磷酸化SD靶向至膜来解释。在膜隔室，它可能整合膜相关的活性信号传导复合物，导致通过磷酸化组蛋白H3染色测量的增殖增加。虽然这些结果是出乎意料的，但它们强调了当用作诱饵分子时防止Src*/SD的膜缔合的重要性。
Elevated expression of p130Cas (Crk-associated substrate)/BCAR1 (breast cancer antiestrogen resistance 1) in human breast tumors is a marker of poor prognosis and poor overall survival. p130Cas is a downstream target of the tyrosine kinase c-Src. Signaling mediated by p130Cas through its phosphorylated substrate domain (SD) and interaction with effector molecules directly promotes tumor progression. We previously developed a constitutively phosphorylated p130Cas SD molecule, Src*/SD (formerly referred to as Src*/CasSD), which acts as decoy molecule and attenuates the transformed phenotype in v-crk-transformed murine fibroblasts and human breast cancer cells. To test the function of this moleculein vivo, we established mouse mammary tumor virus (MMTV)-long terminal repeat-Src*/SD transgenic mice in which mammary gland development and tumor formation were analyzed. Transgenic expression of the Src*/SD molecule under the MMTV-long terminal repeat promoter did not interfere with normal mammary gland development or induce tumors in mice observed for up to 11 months. To evaluate the effects of the Src*/SD molecule on tumor developmentin vivo, we utilized the MMTV-polyoma middle T-antigen (PyMT) murine breast cancer model that depends on c-Src. PyMT mice crossed with Src*/SD mice displayed accelerated tumor formation. The earlier onset of tumors can be explained by the interaction of the Src* domain with PyMT and targeting the fused phosphorylated SD to the membrane. At membrane compartments, it might integrate membrane-associated active signaling complexes leading to increased proliferation measured by phospho-Histone H3 staining. Although these results were unexpected, they emphasize the importance of preventing the membrane association of Src*/SD when employed as decoy molecule.
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影响因子：
4.8
作者：
Kumbrink, Joerg;Kirsch, Kathrin H.
通讯作者：
Kirsch, Kathrin H.
影响因子：
8
作者：
Hart, KC;Donoghue, DJ
通讯作者：
Donoghue, DJ
影响因子：
14.5
作者：
Cheng J;DeCaprio JA;Fluck MM;Schaffhausen BS
通讯作者：
Schaffhausen BS
DOI：
10.1016/j.biocel.2012.12.017
发表时间：
2013-03
期刊：
The international journal of biochemistry & cell biology
影响因子：
--
作者：
Kumbrink J;Kirsch KH
通讯作者：
Kirsch KH
影响因子：
11.2
作者：
Hulit, James;Suyama, Kimita;Hazan, Rachel B.
通讯作者：
Hazan, Rachel B.