Biology and physiology of Calbindin-D9k in female reproductive tissues: Involvement of steroids and endocrine disruptors

A 9-kilodalton cytosolic calcium-binding protein termed as Calbindin-D9k (CaBP-9k) belongs to a family of intracellular proteins which have high affinities for calcium, and has two calcium binding domains [1]. The full-length cDNA encoding the human CaBP-9k has been cloned using reverse transcription/PCR, which includes coding region of 79 amino acids, 57 nucleotides 5'- and 159 nucleotides 3'-non-coding region, and a poly(A) tail (total 600 nucleotides in length) [2]. Further, our study revealed that this gene spans about 5.5-kb and is localized on the X-chromosome, consists of three exons and carries four Alu repeats [3]. In addition to its genomic structure, a sequence of 50 nucleotides downstream from the promoter showed an extensive homology to the estrogen response element (ERE) at the same location within the rat calbindin-D9k gene, suggesting that a two-nucleotide change within this region in human causes the gene to lack expression in human uterus and placenta [3].It has been demonstrated that CaBP-9k is expressed in diverse mammalian tissues, i.e., intestine, uterus, kidney, and bone [4-7]. The functional role of CaBP-9k is involved in intestinal calcium absorption and its gene is regulated at the transcriptional or post-transcriptional level by 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), a hormonal form of vitamin D [8,9]. This hormonal form caused a parallel increase in CaBP-9k mRNA and intestinal absorption of calcium in rats [10]. In addition, uterine CaBP-9k may be involved in controlling myometrial activity related with intracellular calcium level [6], but an exact role of CaBP-9k in the uterus is still under investigation by us and a few of other research groups. Recently, we demonstrated that uterine CaBP-9k is responsive to exogenous estrogen (E2) and can be a biomarker for environmental estrogenic chemicals, so called as "endocrine disruptors" in rat models [11-15]. Thus, in this review, we summarize recent research literature in regards to the expr