IFN-gamma regulation of vacuolar pH, cathepsin D processing and autophagy in mammary epithelial cells.
IFN-gamma regulation of vacuolar pH, cathepsin D processing and autophagy in mammary epithelial cells.
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DOI：
10.1002/jcb.21814
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发表时间：
2008-09-01
影响因子：
4
通讯作者：
Hendrix, Mary J. C.
中科院分区：
文献类型：
--
作者：
Khalkhali-Ellis, Zhila;Abbott, Daniel E.;Bailey, Caleb M.;Goossens, William;Margaryan, Naira V.;Gluck, Stephen L.;Reuveni, Moshe;Hendrix, Mary J. C.
在这项研究中，我们检测了干扰素-γ (IFN-γ)调节乳腺上皮细胞生长和基因表达的能力，特别强调了两个基因：Maspin（丝氨酸蛋白酶抑制剂超家族成员）和溶酶体天冬氨酸内肽酶组织蛋白酶D （CatD）。这些基因的蛋白产物在乳腺组织发育和重塑的不同阶段的多种生物学功能的调控中起着关键作用。此外，Maspin在原发性乳腺癌中表达下调，在转移性乳腺癌中表达缺失，而CatD在乳腺癌细胞中过量产生并异常分泌。我们报道IFN-γ受体在乳腺上皮细胞中表达，IFN-γ受体通过Stat-1传导IFN-γ信号，导致液泡pH降低。液泡pH的变化改变了CatD蛋白的加工和分泌，同时增加了Maspin的分泌。此外，IFN-γ对乳腺上皮细胞的生长和增殖具有抑制作用，并诱导其形态学改变。我们的研究还表明，缺乏Maspin的乳腺癌细胞在液泡pH和CatD的变化方面对IFN-γ具有难耐性。然而，Maspin转染乳腺癌细胞会部分使细胞对IFN-γ的作用敏感，从而提供新的治疗意义。
In this study we examined the ability of interferon-γ (IFN-γ) to regulate mammary epithelial cell growth and gene expression, with particular emphasis on two genes: Maspin (a member of serine protease inhibitor superfamily), and the lysosomal aspartyl endopeptidase cathepsin D (CatD). The protein products of these genes are critically involved in regulation of multitude of biological functions in different stages of mammary tissue development and remodeling. In addition, the expression of Maspin is down-regulated in primary breast cancer and is lost in metastatic disease, while CatD is excessively produced and aberrantly secreted by breast cancer cells. We report that IFN-γ receptors are expressed in mammary epithelial cells, and receptor engagement by IFN-γ transduces the IFN-γ signal via Stat-1 resulting in decreased vacuolar pH. This change in vacuolar pH alters CatD protein processing and secretion concurrent with increased Maspin secretion. In addition, IFN-γ exerts a suppressive effect on cell growth and proliferation, and induces morphological changes in mammary epithelial cells. Our studies also reveal that breast cancer cells, which are devoid of Maspin, are refractory to IFN-γ with respect to changes in vacuolar pH and CatD. However, Maspin transfection of breast cancer cells partially sensitizes the cells to IFN-γ’s effect, thus providing new therapeutic implications.
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