Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P56851 (epididymal)
 11,273 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has recently been shown that chimeric toxins composed of acidic fibroblast growth factor fused to mutant forms of Pseudomonas exotoxin (aFGF-PE) are cytotoxic to a variety of tumor cell lines with FGF receptors. Although aFGF-PE might be considered as a possible chemotherapeutic toxin, limited knowledge is available concerning its effect on endothelia. This study investigates whether one of the aFGF-PE fusion proteins, aFGF-PE664GluKDEL, can function as an anti-angiogenic agent. Protein synthesis studies using rat epididymal fat pad microvascular endothelial cells (RFCs) indicated that after 24 h in culture, aFGF-PE had a significant inhibitory effect on protein synthesis at concentrations greater than 100 ng/ml. In cultures incubated with 1000 ng/ml aFGF-PE, RFC protein synthesis was inhibited as much as 83%. RFCs were also cultured in a 3-dimensional type I collagen gel and incubated with either transforming growth factor beta 1, aFGF-PE, or a combination of both. Transforming growth factor beta 1 elicits in vitro angiogenesis in these 3-dimensional cultures which consist of rapid formation of complex tubular structures. Transforming growth factor beta 1-treated RFCs incubated with aFGF-PE were unable to produce this angiogenic response, nor were they able to migrate out of the 3-dimensional culture to form a monolayer as shown by controls. Cell viability analyses showed that aFGF-PE produced a dose-dependent toxic effect which ranged from 10 to 90% cell death. Competition assays in which the chimeric toxin was preincubated with antibodies to aFGF resulted in an 89% reversal of the inhibitory effects of aFGF-PE on endothelial cells. Acidic FGF-PE with a mutation in the ADP ribosylation domain of PE was inactive in both 2-dimensional and 3-dimensional cultures. These data show that aFGF-PE has specific in vitro cytotoxic, antiangiogenic, and antimigratory effects on microvascular endothelia.
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PMID:Acidic fibroblast growth factor-Pseudomonas exotoxin chimeric protein elicits antiangiogenic effects on endothelial cells. 138 Dec 75

The objective of this study was to test the hypothesis that gamma-glutamyl transpeptidase (GGT) catalytic activity and protein level in the initial segment are regulated by testicular factors. In the rat epididymis, levels of GGT catalytic activity were initial segment > caput > corpus = cauda. GGT catalytic activity and protein level in the initial segment decreased after efferent duct ligation (EDL) for 3 days, but were recovered when initial segment pieces were incubated with ovine or rat rete testis fluid (oRTF or rRTF, respectively). Factors responsible for the recovery were shown to be greater than 10 kDa and protein-like, but these factors were not androgen-binding protein or testosterone in oRTF. Further experiments were designed to test the hypothesis that growth factors within oRTF and rRTF regulate GGT catalytic activity and GGT protein level. Basic fibroblast growth factor (bFGF) but not epidermal growth factor recovered GGT catalytic activity and protein level in the initial segment following 3-day EDL. Western blot analyses also revealed that bFGF-like proteins were present in rRTF, epididymal luminal fluid, and rat initial segment homogenate, and that the level of bFGF-like proteins declined in the initial segment following 3-day EDL. Using a bFGF monoclonal antibody, a small amount of bFGF-like proteins was found to be also present in oRTF. Our studies suggest that bFGF is one of the testicular factors involved in the regulation of epididymal GGT catalytic activity and protein level. Since decreased GGT catalytic activity caused by 3-day EDL in the rat initial segment was also recovered by a tumor promoter, phorbol 12-O-tetradecanoylphorbol 13-acetate, it is possible that a signal transduction pathway is involved in the regulation of GGT catalytic activity and GGT protein level by testicular factors. Western blot analyses also indicated that the 43-kDa bFGF-like protein in the lumen of the rat epididymis originates from the testis, is concentrated in the initial segment, and is reabsorbed by the epididymal epithelia from proximal to distal epididymal regions.
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PMID:Regulation of gamma-glutamyl transpeptidase catalytic activity and protein level in the initial segment of the rat epididymis by testicular factors: role of basic fibroblast growth factor. 947 41

Normal epididymal function is regulated by androgens and testicular factors. Our studies have been directed towards identifying testicular factors that regulate the function of the initial segment and the mechanisms by which this is achieved. The initial segment appears to be critical for normal sperm maturation in view of recent gene knock-out studies. Previous and ongoing studies from this and other laboratories have shown that the expression of several genes including proenkephalin, cystatin-related epididymal specific (CRES), 5 alpha-reductase and gamma-glutamyl transpeptidase (GGT) within the initial segment is highly dependent upon the presence of testicular factors. A lumicrine mechanism of regulation of these genes is proposed. The regulation of gamma-glutamyl transpeptidase (GGT) is described as a model enzyme for studying the role and identification of testicular factors. GGT appears to play an important role in the protection of spermatozoa from oxidative stress. Multiple GGT mRNAs (II-IV) are expressed within the epididymis, but GGT mRNA IV is the only form that is highly expressed in the initial segment, especially within zone 1A, and is regulated by testicular factors. Testicular factors control this transcript by regulating both its rate of transcription and its stability. Evidence is presented to suggest that basic fibroblast growth factor (bFGF) is a candidate testicular factor that regulates GGT activity in the epididymis. Basic FGF may regulate gene expression in the epididymis via the ras-raf-MAPK second messenger pathway and by members of the Ets transcription family.
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PMID:Testicular regulation of epididymal gene expression. 1064 65

Dihydrotestosterone (DHT) is the primary androgen acting in the epididymis, the site of sperm maturation. Previously, we showed that the treatment of male rats with PNU157706, an inhibitor that acts on both isoforms of 5alpha-reductase to prevent DHT formation, has effects on the expression of genes implicated in processes that create the optimal luminal microenvironment required for sperm maturation, and on sperm maturation itself. However, signaling pathways involved in regulating or mediating DHT actions in the epididymis remain largely unknown. The goals of this study were to determine the expression profiles of potential signaling systems in the epididymis and assess their DHT-dependence using two different dual 5alpha-reductase inhibitors. Rats were untreated or gavaged with vehicle, 10 mg/kg per day PNU157706 or 32 mg/kg per day FK143 for 28 days and epididymal gene expression was analyzed. Gene array analysis revealed analogous effects of FK143 on overall epididymal gene expression when compared with previous PNU157706 studies. Quantitative RT-PCR analysis of the expression of the 5alpha-reductase isozymes, androgen receptor, and members of the IGF, FGF, TGF, and VEGF families revealed novel region-specific expression profiles in the epididymis that were differentially affected by 5alpha-reductase inhibition; the two inhibitors had parallel effects. Specifically, in proximal regions, 5alpha-reductase 1, androgen receptor, and TGF-beta1 expression increased after treatment, while in distal regions expression of IGF-I, IGFBP-5, IGFBP-6, and FGF-10 decreased. These results provide insight into epididymal signaling mechanisms and indicate potential candidates acting either upstream or downstream of DHT to regulate and/or mediate its actions in the epididymis.
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PMID:Region-specific expression of androgen and growth factor pathway genes in the rat epididymis and the effects of dual 5alpha-reductase inhibition. 1700 79

Transgenic (Tg) mice expressing human fibroblast growth factor 8b (FGF8-b) under the probasin promoter (Tg [Pbsn-FGF8] L2-L5Elo; hereafter referred to as FGF8-b-Tg) were shown to produce FGF8-b at high levels in the prostate and epididymis and at lower levels in the testis. The present study examined the effects of FGF8-b expression on the epididymis and testis. In old (age, >6 mo) FGF8-b-Tg mice, epididymides were frequently enlarged, with epithelial and stromal hypercellularity progressing upon aging to epithelial dysplasia and malignant transformation of stroma. In addition, oligospermia, dilatation of the duct, and inflammation were frequently observed in the epididymides. In association with the epididymal changes, some FGF8-b-Tg mice presented a degenerative seminiferous epithelium of the testis. Consistent with this observation, infertile males were found in two FGF8-b-Tg mouse lines. Masson trichrome staining and immunohistochemical analysis of smooth muscle actin, laminin, and androgen receptor revealed that changes in the epididymal stroma closely resembled those previously found in the prostates of the FGF8-b-Tg mice. Genes previously found to be upregulated in the prostate of FGF8-b-Tg mice, such as osteopontin (Spp1) connective tissue growth factor (Ctgf), apolipoprotein D (Apod), and FGF receptor 1c (Fgfr1-c), were also upregulated in the epididymides, suggesting that similar molecular mechanisms were active in both tissues. However, unlike in the prostate, the changes in the epididymal epithelium of the FGF8-b-Tg mice did not progress into invasive carcinoma. The results suggest that prolonged and enhanced FGF signaling induces dramatic changes in the epididymis and testis that lead to infertility in a portion of the FGF8-b-Tg males.
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PMID:Fibroblast growth factor 8b causes progressive stromal and epithelial changes in the epididymis and degeneration of the seminiferous epithelium in the testis of transgenic mice. 2242 49