Apoptosis‐ and endoplasmic reticulum stress‐related genes were regulated by estrogen and progesterone in the uteri of calbindin‐D_9kand ‐D_28kknockout mice

Abstract

Calcium (Ca(2+)) is an important regulator of apoptotic signaling. Calbindin-D(9k) (CaBP-9k) and -D(28k) (CaBP-28k) have a high affinity for Ca(2+) ions. Uterine calbindins appear to be involved in the regulation of myometrial activity by intracellular Ca(2+). In addition, uterine calbindins are expressed in the mouse endometrium and are regulated by steroid hormones during implantation and development. The aim of the present study was to evaluate the regulation of apoptosis in the uteri of CaBP-9k, CaBP-28k, and CaBP-9k/28k knockout (KO) mice. Our findings indicated that Bax protein was enhanced in the uteri of CaBP-28k and CaBP-9k/28k KO mice compared to wild-type (WT) and CaBP-9k KO mice, but no difference was observed in Bcl-2 protein expression. The expressions of caspase 3, 6, and 7 proteins were higher in both CaBP-28k and CaBP-9k/28k KO mice than in WT and CaBP-9k KO mice. These results suggest that the absence of CaBP-28k increases apoptotic signaling. We also investigated the expression of endoplasmic reticulum (ER) stress genes by Western blot analysis in calbindin KO mice. C/EBP homologous protein and immunoglobulin heavy chain-binding protein protein levels were elevated in CaBP-28k KO mice compared to WT mice. When immature mice were treated with 17β-estradiol (E2) or progesterone (P4) for 3 days, we found that the expressions of Bax and caspase 3 protein were increased by E2 treatment in WT and CaBP-9k KO mice, and by P4 treatment in CaBP-28k KO mice. These results indicate that CaBP-28k blocks the up-regulation of apoptosis-related genes and ER stress genes, implying that CaBP-28k may decrease the expression of genes involved in apoptosis and ER stress in murine uterine tissue.

Crucial role of calbindin-D28k in the pathogenesis of Alzheimer’s disease mouse model

“…11, 19 CB overexpression has been reported to block apoptotic cell death in lymphocytes, glial cells and the uteri. 9, 10, 20 However, there is no direct evidence that CB has a role in neuronal apoptosis in AD. To address this question, CBKOTg is one of the best models to show the role of CB in neuronal apoptosis in the brains of Tg mice.…”

“…These findings are consistent to earlier reports that CB protects against apoptotic cell death brought on by A β in both neuronal and glial cells, and that bax and caspase-3 proteins are upregulated by CBKO in the murine uterus. 8, 9, 10 Therefore, it is reasonable to suggest that CB expression may contribute to neuronal survival in Tg mice. During apoptosis, remodeling of the mitochondrial cristae is accompanied by fragmentation of the mitochondria network.…”

“…For example, overexpression of CB inhibited apoptotic activities induced by A β and mutant presenilin-1 (PS1) in glial and neuronal cells 8, 9 and bax or caspase-3-related apoptotic signaling was increased in uteri of CB knock-out (CBKO) mice. 10 It has been reported that the deficits of learning in mice expressing the familial AD-mutant hAPP correlated strongly with decreased levels of CB in the dentate gyrus of the brain. 11 Furthermore, homozygous CBKO mice displayed impairments in motor coordination and activity.…”

The roles of endoplasmic reticulum stress response in female mammalian reproduction

“…Therefore, our limited knowledge leads us to speculate that calcium regulates embryo implantation through ERS and the UPR. Indeed, the expression of ERS genes in the uterus is changed in calbindin-D(9 k) and -D(28 k) knockout mice (Jung et al 2012).…”

“…E 2 induces apoptosis of the uterine epithelium, whereas P 4 represses it (Terada et al 1989). P 4 is induced by the ERS response pathway (Jung et al 2012).…”