文章：

p160类固醇受体共激活物（SRC）家族的正常和癌症相关功能

Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family

原文发布日期：2009-09-01

DOI: 10.1038/nrc2695

类型: Review Article

开放获取: 否

要点：

1. SRC1 was the first cloned steroid receptor co-activator that interacts with steroid hormone receptors to promote transcriptional activation in a hormone-dependent manner.
2. The p160 SRC family contains three homologous members, SRC1, SRC2 and SRC3, that interact with nuclear receptors and specific transcription factors. They recruit chromatin remodelling and other transcriptional enzymes to facilitate the assembly of general transcription factors for transcriptional activation.
3. SRCs are post-translationally modified in response to several upstream signalling pathways. These post-translational modifications determine or modulate SRC stability, subcellular localization, functional specificity, co-activator activity and/or co-activator complex assembly or disassembly.
4. SRC-knockout mice show that SRCs are involved in many physiological processes and each SRC has both specific and redundant physiological functions in embryonic and adult tissues.
5. SRC1 expression is increased in a subset of breast cancers and is positively correlated with ERBB2 positivity and poor disease-free survival rate. Knockdown of SRC1 in breast cancer cells inhibits cell proliferation.
6. Knockout of Src1 in mouse mammary tumour virus (MMTV)–polyoma middle T (PyMT) mice suppresses metastasis without affecting primary tumour formation. SRC1 promotes breast cancer metastasis by upregulating ERBB2, colony stimulating factor 1 and TWIST1 expression.
7. Both gene amplification and overexpression of SRC3 occur in a subset of breast cancers. SRC3 overexpression usually correlates with the expression of ERBB2, matrix metalloproteinase 2 (MMP2), MMP9 and polyoma enhancer activator 3, and with larger tumour size, higher tumour grade and/or poor disease-free survival.
8. SRC3 has an important role in promoting breast tumour cell proliferation, migration, invasion and metastasis through many mechanisms, such as increasing the function of oestrogen receptor-α and E2F1, the activity of the insulin-like growth factor 1 (IGF1) signalling pathway, epidermal growth factor receptor (EGFR) and ERBB2, and the expression of MMPs.
9. Knockout of Src3 in mice suppresses mammary tumour initiation, growth and metastasis, and overexpression of SRC3 in mouse mammary epithelial cells is sufficient to induce spontaneous mammary tumorigenesis.
10. SRC3 expression is increased during prostate tumorigenesis in mice. Knockout of Src3 efficiently arrests prostate tumour progression at a well-differentiated stage.

要点翻译：

1. SRC1是首个被克隆的类固醇受体共激活因子，它能与类固醇激素受体相互作用，以激素依赖的方式促进转录激活。
2. p160 SRC家族包含三个同源成员：SRC1、SRC2和SRC3，它们与核受体及特定转录因子相互作用。这些成员通过招募染色质重塑复合物和其他转录相关酶类，促进通用转录因子的组装以实现转录激活。
3. SRC家族蛋白会响应多种上游信号通路发生翻译后修饰。这些修饰决定或调控着SRC蛋白的稳定性、亚细胞定位、功能特异性、共激活活性及共激活复合体的组装或解聚。
4. SRC基因敲除小鼠研究表明，SRC家族参与多种生理过程，每个成员在胚胎和成年组织中既具有特异性功能，也存在功能冗余。
5. 在部分乳腺癌中SRC1表达升高，且与ERBB2阳性及较低的无病生存率呈正相关。在乳腺癌细胞中敲低SRC1可抑制细胞增殖。
6. 在MMTV-PyMT小鼠模型中敲除Src1可抑制肿瘤转移，但不影响原发瘤形成。SRC1通过上调ERBB2、集落刺激因子1和TWIST1的表达促进乳腺癌转移。
7. 部分乳腺癌中存在SRC3基因扩增和过表达现象。SRC3过表达通常与ERBB2、基质金属蛋白酶2（MMP2）、MMP9及多瘤增强子激活因子3的表达相关，并与更大肿瘤体积、更高肿瘤分级和/或较差无病生存率相关。
8. SRC3通过多种机制促进乳腺肿瘤细胞增殖、迁移、侵袭和转移，包括增强雌激素受体-α和E2F1功能、提高胰岛素样生长因子1（IGF1）信号通路活性、激活表皮生长因子受体（EGFR）和ERBB2，以及上调MMPs表达。
9. 小鼠模型中敲除Src3可抑制乳腺肿瘤的发生、生长和转移，而在小鼠乳腺上皮细胞中过表达SRC3足以诱导自发性乳腺肿瘤生成。
10. 在前列腺肿瘤发生过程中，小鼠模型的SRC3表达逐渐升高。敲除Src3能有效阻止前列腺肿瘤进展，使其停滞在高分化阶段。

英文摘要：

The three homologous members of the p160 SRC family (SRC1, SRC2 and SRC3) mediate the transcriptional functions of nuclear receptors and other transcription factors, and are the most studied of all the transcriptional co-activators. Recent work has indicated that the SRCgenes are subject to amplification and overexpression in various human cancers. Some of the molecular mechanisms responsible for SRC overexpression, along with the mechanisms by which SRCs promote breast and prostate cancer cell proliferation and survival, have been identified, as have the specific contributions of individual SRC family members to spontaneous breast and prostate carcinogenesis in genetically manipulated mouse models. These studies have identified new challenges for cancer research and therapy.

摘要翻译： 

p160 SRC家族（SRC1、SRC2和SRC3）的三个同源成员介导核受体和其他转录因子的转录功能，是所有转录共激活因子中研究最为深入的。近期研究表明，SRC基因在多种人类癌症中存在扩增和过表达。已发现导致SRC过表达的部分分子机制，以及SRC促进乳腺癌和前列腺癌细胞增殖与存活的机制；同时，在基因操作小鼠模型中，也明确了SRC家族各成员对自发性乳腺癌和前列腺癌发生的特异性贡献。这些研究为癌症研究与治疗提出了新的挑战。

原文链接：

Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family