Human endometrium is unique since it is the only tissue in the body that regularly bleeds. In addition, abnormal endometrial bleeding is one of the most common manifestations of gynecological diseases and a prime indication for hysterectomy. A team headed by Tabibzadeh , in the May issue of the Journal of Clinical Investigation, reported a novel human gene, whose strong expression was observed in human endometrium immediately prior to and during menstruation. In addition, this gene was expressed in endometria of patients with active endometrial bleeding regardless of the phase of the menstrual cycle. During the proliferative, early and mid-secretory phases, this gene was not expressed in normal human endometrium. In situ hybridization showed that the mRNA of this so-called endometrial bleeding associated factor (ebaf) was expressed in the endometrial stroma without any discernible mRNA expression in the endometrial glands or endothelial cells. These findings show that the expression of ebaf is intimately linked to normal and abnormal endometrial bleeding.

The predicted protein sequence of ebaf showed a strong homology to the mouse lefty/stra3. ebaf is 77% identical and 83% similar to lefty protein. Most of the cysteine residues which are conserved among the TGF-b related proteins and which are necessary for the formation of the cysteine-knot structure were found in the predicted protein sequence of ebaf. The predicted protein sequence of ebaf contains an additional cysteine residue, 12 amino acids upstream from the first conserved cysteine residue. The only other family members, known to contain an additional cysteine residue, are TGF-bs, inhibins and GDF-3. ebaf, similar to lefty, GDF-3/Vgr2 and GDF-9, lacks the cysteine residue that is known to form the intermolecular disulfide bond. Fluorescent in situ hybridization showed that ebaf gene is located on human chromosome 1 at band q42.1.

In the July 15 issue of "Frontiers in Bioscience" Tabibzadeh et al reported that the expression of ebaf was absent in a host of normal tissues including lung, stomach, small bowel, liver, kidney, breast, lymph node, spleen, ovary and fallopian tube. However, a weak expression of the 2.1 kb variant of the ebaf (ebaf) mRNA was observed in rectal, ovarian, and testicular tissues and the 2.1 and 2.5 kb ebaf (ebaf) mRNAs were observed in the pancreatic tissue. The expression of the mRNA of this gene was absent in sarcomas, Hodgkin's and non-Hodgkin's lymphomas, melanomas, squamous cell carcinomas, hepatocellular carcinomas, renal cell carcinomas, and adenocarcinomas of the breast, endometrium and lung. The expression of the ebaf (ebaf) mRNA was observed primarily in adenocarcinomas that exhibited a mucinous differentiation. This included colonic, duodenal, and ovarian adenocarcinomas. The expression of ebaf (ebaf) mRNA was absent in non-mucinous colonic, gastric and ovarian adenocarcinomas and adenocarcinomas of colon metastatic to the liver. However, some serous adenocarcinomas of the ovary also exhibited ebaf (ebaf) mRNA. The testicular tumors, seminomas and embryonal carcinomas, also expressed ebaf (ebaf) mRNA. These findings show that the ebaf (ebaf) mRNA has a distinct expression in normal and neoplastic tissues.

In situ hybridization of ebaf ebaf mRNA in human endometrium and in adenocarcinomas of colon and ovary. Digoxigenin-labeled anti-sense (A, C, E) and sense RNAs (B, D, F) of ebaf (ebaf) were synthesized by in vitro transcription of the full length ebaf (ebaf) cDNA cloned into pBluescript^R SK(+/-). Sections of a late secretory endometrium were used as the positive control (A). Hybridization signal is seen in the endometrial stroma (A) and in the epithelial cells of a colonic adenocarcinoma with mucinous differentiation (C) and ovarian adenocarcinoma (E). The sense probe did not reveal any hybridization signal in the sections of the endometrium (B) or the same tumors (D, F).

Ravi Kothapalli, Ibrahim Buyuksal, Shi-Qi Wu, Nasser Chegini, Siamak Tabibzadeh: Detection of ebaf, a novel human gene of the TGF-b superfamily; association of gene expression with endometrial bleeding. J Clin Invest 99, 2342-2350 (1997) PMID: 9153275

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