The biologically active metabolite of vitamin D (cholecalciferol), i.e. 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a secosteroid hormone whose mode of action involves stereospecific interaction with an intracellular receptor protein (vitamin D receptor; VDR). 1,25(OH)2D3 is known to be a principal regulator of calcium homeostasis, and it has numerous other physiological functions including inhibition of proliferation of cancer cells, effects on hormone secretion and suppression of T-cell proliferation and cytokine production. Although the exact mechanisms involved in mediating many of the different effects of 1,25(OH)2D3 are not completely defined, genomic actions involving the VDR are clearly of major importance. Similar to other steroid receptors, the VDR is phosphorylated; however, the exact functional role of the phosphorylation of the VDR remains to be determined. The VDR has been reported to be regulated by 1,25(OH)2D3 and also by activation of protein kinases A and C, suggesting co-operativity between signal transduction pathways and 1,25(OH)2D3 action. The VDR binds to vitamin D-responsive elements (VDREs) in the 5' flanking region of target genes. It has been suggested that VDR homodimerization can occur upon binding to certain VDREs but that the VDR/retinoid X receptor (RXR) heterodimer is the functional transactivating species. Other factors reported to be involved in VDR-mediated transcription include chicken ovalbumin upstream promoter (COUP) transcription factor, which is involved in active silencing of transcription, and transcription factor IIB, which has been suggested to play a major role following VDR/RXR heterodimerization. Newly identified vitamin D-dependent target genes include those for Ca2+/Mg(2+)-ATPase in the intestine and p21 in the myelomonocytic U937 cell line. Elucidation of the mechanisms involved in the multiple actions of 1,25(OH)2D3 will be an active area of future research.

Claudins form a large family of tight junction proteins that have essential roles in the control of paracellular ion flux and the maintenance of cell polarity. Many studies have shown that several claudin family members are abnormally expressed in various cancers. In particular, CLDN4 (encoding claudin-4) is overexpressed in ovarian cancer. However, although CLDN4 overexpression is well established, the mechanisms responsible for this abnormal regulation remain unknown. In the present study, we delineate a small region of the CLDN4 promoter critical for its expression. This region contains two Sp1 sites, both of which are required for promoter activity. However, because of the ubiquitous expression of Sp1, these sites, although necessary, are not sufficient to explain the patterns of gene expression of CLDN4 in various ovarian tissues. We show that the CLDN4 promoter is further controlled by epigenetic modifications of the Sp1-containing critical promoter region. Cells that overexpress CLDN4 exhibit low DNA methylation and high histone H3 acetylation of the critical CLDN4 promoter region, and the reverse is observed in cells that do not express CLDN4. Moreover, the CLDN4-negative cells can be induced to express CLDN4 through treatment with demethylating and/or acetylating agents. Because CLDN4 is elevated in a large fraction of ovarian cancer, the mechanism leading to deregulation may represent a general pathway in ovarian tumorigenesis and may lead to novel strategies for therapy and an overall better understanding of the biology of this disease.Claudins are major components of tight junctions, which are essential in the control of paracellular ion flux and the maintenance of cell polarity. The presence of phosphorylation sites and PDZ-binding motifs in claudins suggest a role in signal transduction for these proteins (1-3). So far, 23 members of the claudin family have been identified, and the expression of the various claudins has been shown to vary among or even within tissues, probably depending on the exact physiological requirements (1). The gene for claudin-4, CLDN4, is normally expressed in the epithelial cells of colon mucosa, mammary gland, renal tubules, and thyroid gland.Recently, several claudin genes have been shown to be abnormally expressed in human malignancies (4). In particular, CLDN4 has now been shown to be significantly elevated in several malignancies such as breast, pancreas, prostate, and ovary (4). In ovarian cancer, we and several other groups have shown that the genes for CLDN3 and CLDN4, as well as their corresponding proteins (claudin-3 and -4) are frequently up-regulated (5-10). Because many CA125-negative ovarian cancers overexpress these claudins, they may represent diagnostically useful biomarkers for this disease (11). Furthermore claudin-3 and claudin-4 are receptors for the cytotoxic Clostridium perfringens enterotoxin (12), and intra-abdominal administration of Clostridium perfringens enterotoxin might represent an interesting new avenue for ovarian cancer therapy (13). Alt...

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Background: CD44, a multifunctional receptor, undergoes cleavage to produce an intracytoplasmic domain (CD44-ICD) that translocates into the nucleus. Results: CD44-ICD binds to a novel DNA consensus sequence and activates many genes. Conclusion:We finally explain the multifunctionality of CD44 and reveal new genes affected by CD44. Significance: Our findings will accelerate the understanding of how CD44-ICD regulates a multitude of cell functions.