NCBI Summary:
Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. These junctions are comprised of sets of continuous networking strands in the outwardly facing cytoplasmic leaflet, with complementary grooves in the inwardly facing extracytoplasmic leaflet. The protein encoded by this intronless gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. It is also a low-affinity receptor for Clostridium perfringens enterotoxin, and shares aa sequence similarity with a putative apoptosis-related protein found in rat.
General function
Cell adhesion molecule
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Cellular localization
Plasma membrane
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Ovarian function
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Expression regulated by
FSH, LH
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Rimon E, et al reported
Gonadotropin-induced gene regulation in human granulosa cells obtained from IVF patients and Modulation of genes coding for growth factors and their receptors and genes involved in cancer and other diseases.
Gonadotropins play a crucial role in ovarian homeostasis and fertilization. However, hypergonadotropin stimulation has been thought to increase the risk for ovarian cancer. Moreover, some correlation between high levels of gonadotropins in the circulation and Alzheimer's disease has been implicated, with no clear evidence on the molecular mechanism involved. Using DNA microarray technology and RNA from gonadotropin-stimulated human granulosa cells, which comprise the main bulk of the ovarian follicular somatic cells, we discovered that stimulation of cells with saturating doses of gonadotropins gives rise to the expression of genes coding for presenilin 1 and 2, along with the up-regulation of genes involved in steroidogenesis such as StAR, cytochrome P450scc enzyme system and aromatase. Moreover, gonadotropin stimulation in these cells dramatically elevates activity of genes coding for epiregulin and amphiregulin, which can bind and activate the EGF receptor and ERB4. These gene products may elevate the risk for ovarian, breast, endometrial and other non-gynecological cancers. Gene transcripts for oncogenes and tumor markers such as pleiomorphic adenoma gene-like 1 (Plagl1) tumor antigen (L6) and claudin 3 were markedly elevated following LH and FSH stimulation. In parallel, downregulation in ovarian cancer 1 (DOC1) and suppression of tumorigenicity (ST5) genes was observed, suggesting a potential increase for cancer development. In contrast, increase in tumor rejection antigen (gp96) 1 and decrease in connective tissue growth factor (CTGF), transforming growth factor-beta 1 induced transcript 1 (TGFB1Il), pim-1 oncogene (PIM1), v-maf musculoaponeurotic fibrosarcoma oncogene homologue (MAF) and CD24 antigen may be associated with a decreased risk for specific cancers. In conclusion, gonadotropin stimulation may modulate specific sets of gene transcripts that may either elevate or reduce the risk for specific diseases.
Ovarian localization
Granulosa
Comment
Rangel LB, et al reported that tight junction proteins claudin-3 and claudin-4 are frequently overexpressed in
ovarian cancer but not in ovarian cystadenomas.
Because
claudin-3 and claudin-4 have been proposed to be expressed in epithelial ovarian cancer, we have
performed a detailed analysis of CLDN3 and CLDN4 expression in a panel of ovarian tumors of
various subtypes and cell lines. We also investigated whether high expression of claudin-3 and
claudin-4 was associated with TJ function in ovarian cancer cells. RNA was
obtained from a panel of 39 microdissected epithelial ovarian tumors of various histological
subtypes for real-time reverse transcription-PCR analysis. In addition, a total of 70 cases of ovarian
carcinomas, ovarian cysts, and normal ovarian epithelium from a tissue array were analyzed by
immunohistochemistry. Finally, a panel of cell lines was used for Western analysis of claudin
expression and TJ permeability studies. RESULTS: Although expressed at low levels in some
normal human tissues, including the ovary, CLDN3 and CLDN4 are highly up-regulated in epithelial
ovarian cancers of all subtypes. Immunohistochemical analyses using our ovarian tissue array
confirmed the high level of expression of claudin-3 and claudin-4 in the majority of ovarian
carcinomas, including many tumors exhibiting cytoplasmic staining. Ovarian cystadenoma did not
frequently overexpress these proteins, suggesting that the expression of these proteins is associated
with malignancy. In ovarian cancer cell lines, claudin-3 and claudin-4 expression was not
associated with functional TJs as measured by transepithelial electrical resistance.
CONCLUSIONS: These results show that CLDN3 and CLDN4 are frequently up-regulated in
ovarian tumors and cell lines and may represent novel markers for this disease. Overexpression of
these genes in ovarian cancer also suggests interesting scenarios for the involvement of TJ in
tumorigenesis. A better knowledge of the mechanisms underlying ovarian tumorigenesis will likely
result in the development of novel approaches for the diagnosis and therapy of this deadly disease.