Kawamura Kazuhiro, Fukuda Jun, Shimizu Yasushi, Kodama Hideya, Tanaka Toshinobu
Department of Obstetrics and Gynecology, Akita University School of Medicine, Japan.
Biol Reprod. 2005 Dec;73(6):1094-101. doi: 10.1095/biolreprod.105.042754. Epub 2005 Aug 3.
Transforming growth factor alpha (TGFA) is produced by epithelial cells in the oviducts and uteri and has the potential to act as an anti-apoptotic factor on preimplantation embryos expressing its receptor. Previously, we demonstrated that survivin (also known as BIRC5), an anti-apoptotic gene expressed in mouse preimplantation embryos, protects embryos from apoptosis. In this study, we investigated the role of survivin on TGFA-mediated inhibition of apoptosis in mouse blastocysts. Under the suboptimal conditions produced by single embryo culture, blastocysts showed an increase of apoptosis that correlated with a decrease of survivin expression. TGFA treatment significantly decreased apoptosis and increased the levels of survivin mRNA in a dose-dependent manner in blastocyst, and conversely, these activities were neutralized by an anti-TGFA antibody. Antibody treatment alone exerted little effect on either the occurrence of apoptosis or the levels of survivin mRNA. Upregulation of survivin expression by TGFA treatment was insignificant before the blastocyst stage. Using an antisense approach, we examined whether upregulation of survivin is responsible for the anti-apoptotic effect of TGFA in blastocysts. Apoptosis was inhibited by TGFA treatment in blastocysts, but the effect was abrogated by cotreatment with antisense oligonucleotides directed against survivin. These data suggest that survivin contributes to the anti-apoptotic activities of TGFA in blastocysts. We also found that the upregulation of survivin expression was mediated by activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Thus, TGFA inhibits apoptosis in mouse blastocysts through upregulation of survivin expression via the PI3K pathway.
转化生长因子α（TGFA）由输卵管和子宫中的上皮细胞产生，对表达其受体的植入前胚胎具有抗凋亡因子的作用。此前，我们证明了存活素（也称为BIRC5），一种在小鼠植入前胚胎中表达的抗凋亡基因，可保护胚胎免于凋亡。在本研究中，我们调查了存活素在TGFA介导的小鼠囊胚凋亡抑制中的作用。在单胚胎培养产生的次优条件下，囊胚的凋亡增加，这与存活素表达的降低相关。TGFA处理显著降低了囊胚的凋亡，并以剂量依赖的方式增加了存活素mRNA的水平，相反，这些活性被抗TGFA抗体中和。单独的抗体处理对凋亡的发生或存活素mRNA的水平几乎没有影响。在囊胚期之前，TGFA处理导致的存活素表达上调不明显。使用反义方法，我们研究了存活素的上调是否是TGFA在囊胚中抗凋亡作用的原因。TGFA处理可抑制囊胚的凋亡，但与针对存活素的反义寡核苷酸共同处理可消除这种作用。这些数据表明，存活素有助于TGFA在囊胚中的抗凋亡活性。我们还发现，存活素表达的上调是由磷脂酰肌醇3激酶（PI3K）信号通路的激活介导的。因此，TGFA通过PI3K途径上调存活素表达来抑制小鼠囊胚的凋亡。
