Role of DDC-4/sFRP-4, a secreted Frizzled-related protein, at the onset of apoptosis in mammary involution
Role of DDC-4/sFRP-4, a secreted Frizzled-related protein, at the onset of apoptosis in mammary involution
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DOI：
10.1038/sj.cdd.4401197
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发表时间：
2003-05-01
影响因子：
12.4
通讯作者：
Friis, R
中科院分区：
文献类型：
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作者：
Lacher, MD;Siegenthaler, A;Friis, R
利用差分显示技术，我们分离了DDC-4，这是一种分泌性卷曲相关蛋白（sFRP），可诱导激素调节的生殖组织（如乳腺、前列腺、黄体和子宫）的生理性凋亡。我们在异位DDC-4/sFRP-4过表达的动物中研究了该基因在细胞凋亡中的作用。在MMTV-LTR启动子控制下，携带DDC-4/sFRP-4 cDNA的转基因小鼠在妊娠第19天至哺乳第4天期间出现泌乳不足，肺泡中出现大量凋亡细胞，TUNEL反应和活化caspase-3的存在证实了这一点。我们进行了PKB/Akt激酶实验，并使用磷酸化特异性抗体研究了几种底物，发现PKB/Akt本身以及糖原合成酶激酶3 β (gsk -3 β)、BAD和Forkhead的磷酸化程度降低。综上所述，我们的研究结果表明DDC-4/sFRP-4在乳腺复旧开始时破坏上皮细胞存活途径中发挥了作用。
Using differential display, we isolated DDC-4, a secreted frizzled-related protein (sFRP), which is induced in the physiological apoptosis of hormonally regulated, reproductive tissues such as mammary gland, prostate, corpus lute and uterus. The role of this gene in apoptosis was studied in animals overexpressing ectopic DDC-4/sFRP-4. Transgenic mice bearing the DDC-4/sFRP-4 cDNA under the control of the MMTV-LTR promoter showed lactational insufficiency and many apoptotic cells in the alveoli between day 19 of pregnancy and day 4 of lactation as demonstrated by TUNEL reaction and the presence of activated caspase-3. We performed a PKB/Akt kinase assay and studied several of its substrates using phosphorylation-specific antibodies to show reduced phosphorylation in PKB/Akt itself, as well as in glycogen synthetase kinase-3beta (GSK-3beta), BAD, and Forkhead. Taken together, our results show a role for DDC-4/sFRP-4 in abrogating an epithelial cell survival pathway at the onset of mammary gland involution.