Tumour supressor secreted frizzled related protein 1 regulates p53-mediated apoptosis
Tumour supressor secreted frizzled related protein 1 regulates p53-mediated apoptosis
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DOI：
10.1002/cbin.10176
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发表时间：
2014-01-01
影响因子：
3.9
通讯作者：
Schneider, Sallie S.
中科院分区：
文献类型：
--
作者：
Gauger, Kelly J.;Schneider, Sallie S.
乳腺癌是女性最常见的癌症，也是女性癌症死亡的第二大原因。癌症是由促进细胞增殖和减少细胞程序性死亡(细胞凋亡)的细胞突变引起的。分泌型卷曲相关蛋白(SFRP)是一个蛋白质家族，以负向调节Wnt信号级联反应的能力而闻名。SFRP1在包括乳腺癌在内的多种癌症中都有表达，在体外，SFRP1下调可减少细胞凋亡，但其机制尚不清楚，体内SFRP1缺陷对乳腺上皮细胞凋亡的影响也不清楚。我们的数据显示，SFRP1(-/-)小鼠的乳腺对DNA损伤的反应是Bcl2L11(Bim)和Bax mRNA的表达显著减少。采用原位末端标记法和裂解半胱氨酸天冬氨酸氨基转移酶-3免疫组织化学方法检测SFRP1缺失在减量照射诱导细胞凋亡中的作用。研究结果表明，SFRP1(-/-)小鼠的DNA片段化较少，而caspase-3的表达减少，P53的表达普遍减少。重组SFRP1可替代内源性表达，提高SFRP1(-/-)小鼠乳腺上皮细胞促凋亡和P53基因表达水平(Bcl21、Bax、CDKN1A和BBC3)。因此，SFRP1在体内介导乳腺上皮细胞对DNA损伤的凋亡反应中起重要作用。SFRP1在P53靶基因表达中的作用也被注意到，这一途径可能值得探索新的治疗方法。
The most frequently occurring cancer in women, and the second leading cause of cancer death among women, is breast cancer. Cancer results from cellular mutations that enhance proliferation and decrease programmed cell death (apoptosis). Secreted frizzled-related proteins (SFRPs) are a family of proteins known for their ability to negatively modulate the Wnt signalling cascade. SFRP1 expression is lost in a multitude of cancers, including breast cancer, and SFRP1 down regulation reduces apoptosis in vitro but the mechanisms remain unclear, as also the effect of Sfrp1 deficiency on apoptosis on mammary epithelial cells in vivo. Our data show that mammary glands from Sfrp1(-/-) mice express significantly less Bcl2l11 (Bim) and Bax mRNA in response to DNA damage. The effect of Sfrp1 loss in reducing -irradiation induced apoptosis was examined by TUNEL staining and cleaved-caspase-3 immunostaining. The findings show that Sfrp1(-/-) mice have less DNA fragmentation, whilst caspase-3 expression is decreased, and that p53 expression is generally diminished. Recombinant SFRP1 could replace endogenous expression and elevate the levels of pro-apoptotic and p53-mediated gene expression (Bcl2l, Bax, Cdkn1a and Bbc3) in mammary epithelial cells derived from Sfrp1(-/-) mice. Thus Sfrp1 plays an important role in mediating mammary epithelial apoptotic response to DNA damage in vivo. The role SFRP1 plays in p53 target gene expression was also noted, which suggests that this pathway may be worth exploiting for novel therapies.