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)

Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, including the glitazone class of drugs, are insulin sensitizers that reduce glucose and lipid levels in patients with type 2 diabetes mellitus. To more fully understand the molecular mechanisms underlying their therapeutic actions, we have characterized the effects of the potent, tyrosine-based PPAR gamma ligand GW1929 on serum glucose and lipid parameters and gene expression in Zucker diabetic fatty rats. In time-course studies, GW1929 treatment decreased circulating FFA levels before reducing glucose and triglyceride levels. We used a comprehensive and unbiased messenger RNA profiling technique to identify genes regulated either directly or indirectly by PPAR gamma in epididymal white adipose tissue, interscapular brown adipose tissue, liver, and soleus skeletal muscle. PPAR gamma activation stimulated the expression of a large number of genes involved in lipogenesis and fatty acid metabolism in both white adipose tissue and brown adipose tissue. In muscle, PPAR gamma agonist treatment decreased the expression of pyruvate dehydrogenase kinase 4, which represses oxidative glucose metabolism, and also decreased the expression of genes involved in fatty acid transport and oxidation. These changes suggest a molecular basis for PPAR gamma-mediated increases in glucose utilization in muscle. In liver, PPAR gamma activation coordinately decreased the expression of genes involved in gluconeogenesis. We conclude from these studies that the antidiabetic actions of PPAR gamma agonists are probably the consequence of 1) their effects on FFA levels, and 2), their coordinate effects on gene expression in multiple insulin-sensitive tissues.
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PMID:Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor gamma activation has coordinate effects on gene expression in multiple insulin-sensitive tissues. 1118 44

Male "viable motheaten" (me(v)) mice, with a naturally occurring mutation in the gene of the SH2 domain protein tyrosine phosphatase SHP-1, are sterile. Known defects in sperm maturation in these mice correlate with an impaired differentiation of the epididymis, which has similarities to the phenotype of mice with a targeted inactivation of the Ros receptor tyrosine kinase. Ros and SHP-1 are coexpressed in epididymal epithelium, and elevated phosphorylation of Ros in the epididymis of me(v) mice suggests that Ros signaling is under control of SHP-1 in vivo. Phosphorylated Ros strongly and directly associates with SHP-1 in yeast two-hybrid, glutathione S-transferase pull-down, and coimmunoprecipitation experiments. Strong binding of SHP-1 to Ros is selective compared to six other receptor tyrosine kinases. The interaction is mediated by the SHP-1 NH(2)-terminal SH2 domain and Ros phosphotyrosine 2267. Overexpression of SHP-1 results in Ros dephosphorylation and effectively downregulates Ros-dependent proliferation and transformation. We propose that SHP-1 is an important downstream regulator of Ros signaling.
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PMID:Negative regulation of Ros receptor tyrosine kinase signaling. An epithelial function of the SH2 domain protein tyrosine phosphatase SHP-1. 1126 49

As mammalian spermatozoa migrate through the epididymis, they acquire functionality characterized by the potential to express coordinated movement and the competence to undergo capacitation. The mechanisms by which spermatozoa gain the ability to capacitate during epididymal transit are poorly understood. The purpose of this study was to investigate the impact of epididymal maturation on the signal transduction pathways regulating tyrosine phosphorylation, because this process is thought to be central to the attainment of a capacitated state and expression of hyperactivated motility. Western blot and immunocytochemical analyses demonstrated that epididymal maturation in vivo is associated with a progressive loss of phosphotyrosine residues from the sperm head. As cells pass from the caput to the cauda epididymis, tyrosine phosphorylation becomes confined to a narrow band at the posterior margin of the acrosomal vesicle. Epididymal maturation of rat spermatozoa was also associated with an acquired competence to respond to high levels of intracellular cAMP by phosphorylating tyrosine residues on the sperm tail. Immature caput spermatozoa were incapable of exhibiting this response, despite the apparent availability of cAMP and protein kinase A. These findings help to clarify the biochemical changes associated with the functional maturation of spermatozoa during epididymal transit.
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PMID:Impact of epididymal maturation on the tyrosine phosphorylation patterns exhibited by rat spermatozoa. 1131 63

Rat spermatozoa from both the caput and cauda epididymidis were shown to generate superoxide anion (O2-.) both spontaneously and following stimulation with NAD(P)H. Caput spermatozoa gave a significantly greater O2- response to NADPH stimulation than caudal cells, whereas in both cell types the responses to exogenous NADPH and NADH were approximately equivalent. Analysis of H2O2 production revealed that this oxidant was generated only by caudal epididymal cells and only in these cells did the stimulation of reactive oxygen species (ROS) production with NADPH lead to an increase in tyrosine phosphorylation. Stimulation of ROS production with NADPH increased intracellular cyclic adenosine monophosphate (cAMP) levels in both caput and caudal epididymal cells, but only in caudal cells did cAMP stimulate tyrosine phosphorylation, in keeping with the NADPH results. On the basis of these findings we propose that tyrosine phosphorylation in rat spermatozoa is driven by ROS acting via 2 different but complementary mechanisms; O2-. stimulates tyrosine kinase activity indirectly through the elevation of intracellular cAMP while H2O2 acts directly on the kinase/phosphatase system, stimulating the former and inhibiting the latter. Zinc was examined as a potential regulator of this signal transduction cascade and was shown to suppress tyrosine phosphorylation in caput cells but to promote this activity in caudal spermatozoa, possibly through an inhibitory effect on tyrosine phosphatase activity. These results reveal the maturation of a redox-regulated, cAMP-mediated, signal transduction cascade during epididymal transit in the rat that is sensitive to zinc and plays a key role in the control of tyrosine phosphorylation events associated with capacitation.
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PMID:A redox-regulated tyrosine phosphorylation cascade in rat spermatozoa. 1145 58

Epididymal sperm maturation culminates in the acquisition of functional competence by testicular spermatozoa. The expression of this functional state is dependent upon a redox-regulated, cAMP-mediated signal transduction cascade that controls the tyrosine phosphorylation status of the spermatozoa during capacitation. Analysis of superoxide anion (O2(-.)) generation by rat epididymal spermatozoa has revealed a two-component process involving electron leakage from the sperm mitochondria at complexes I and II and a plasma membrane NAD(P)H oxidoreductase. Following incubation in a glucose-, lactate-, and pyruvate-free medium (-GLP), O2(-.) generation was suppressed by 86% and 96% in caput and cauda spermatozoa, respectively. The addition of lactate, malate, or succinate to spermatozoa incubated in medium -GLP stimulated O2(-.) generation. This increase could be blocked by rotenone and oligomycin (R/O) in the presence of malate or lactate but not succinate. Stimulation with all three substrates, as well as spontaneous O2(-.) production in +GLP medium, was blocked by the flavoprotein inhibitor, diphenylene iodonium. Diphenylene iodonium, but not R/O, suppressed NAD(P)H-induced lucigenin-dependent chemiluminescence. This NAD(P)H-dependent enzyme resided in the sperm plasma membrane and its activity was regulated by zinc and uncharacterized cytosolic factors. Reverse transcription-polymerase chain reaction analysis indicated that the sperm NAD(P)H oxidoreductase complex is quite distinct from the equivalent leukocyte system.
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PMID:Analysis of reactive oxygen species generating systems in rat epididymal spermatozoa. 1156 31

Capacitation is a complex series of molecular events that occurs in sperm after epididymal maturation and confers on sperm the ability to fertilize an egg. This process can be mimicked in vitro in defined media, the composition of which is based on the electrolyte concentration of oviductal fluid. In most cases, capacitation media contain energy substrates, such as pyruvate, lactate and glucose, a cholesterol acceptor (usually serum albumin), NaHCO(3), Ca(2+), low K(+), and physiological Na(+) concentrations. The mechanism of action by which these compounds promote capacitation is poorly understood at the molecular level; however, some molecular events significant to the initiation of capacitation have been identified. For example, capacitation correlates with cholesterol efflux from the sperm plasma membrane, increased membrane fluidity, modulations in intracellular ion concentrations, hyperpolarization of the sperm plasma membrane and increased protein tyrosine phosphorylation. These molecular events are required for the subsequent induction of hyperactivation and the acrosome reaction. This review discusses the recent progress that has been made in elucidating mechanisms which regulate sperm capacitation.
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PMID:Novel signaling pathways involved in sperm acquisition of fertilizing capacity. 1173 Sep 11

The plasma membrane over the sperm head of several mammalian species has been shown to express a glycerolphosphatidylinositol-linked hyaluronidase known as PH-20. This protein has been associated with the sperm's interaction with the oocyte cumulus matrix and zona pellucida. The characteristics of PH-20 in equine sperm have not been clearly defined. In this study, ejaculated gel-free semen from five stallions and epididymal sperm from isolated epididymis from 10 stallions was used to characterize the PH-20 activity in equine sperm. Affinity purified anti-equine PH-20 polyclonal antibody was used to immunodetect sperm surface-associated PH-20 and immunolabel whole sperm. The intracellular calcium indicator, Fluo-3, was used to assess sperm intracellular calcium. Stallion sperm express a surface-associated hyaluronidase localized to the posterior sperm head region in ejaculated sperm. Following in vitro capacitation and acrosomal exocytosis, the inner acrosomal membrane (IAM) displays intense hyaluronidase fluorescence suggesting that the IAM and hyaluronidase plays a significant role in zona penetration by sperm. Sperm incubated in hyaluronan (HA)-containing capacitation medium display an elevated intracellular calcium concentration (P<0.01) that is associated with translocation of PH-20 antigenic sites on the sperm surface in addition to increases in protein tyrosine phosphorylation. Caput- and cauda-derived sperm display developmentally unique PH-20 immunofluorescence expression patterns. These data suggest that the differential expression of PH-20 in ejaculated and epididymal sperm could be involved in cumulus penetration, sperm-egg recognition, and oolemmal fusion in this species.
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PMID:Equine sperm-oocyte interaction: the role of sperm surface hyaluronidase. 1174 73

Differentiation of spermatids into spermatozoa is regulated via phosphorylated RNA-binding proteins that modulate the expression of stage-specific mRNAs. We demonstrate that the phosphoserine, -threonine or -tyrosine, interaction protein, Styx, complexes with a testicular RNA-binding protein and is essential for normal spermiogenesis. Ablation of Styx expression in mouse disrupts round and elongating spermatid development, resulting in a >1,000-fold decrease in spermatozoa production. Moreover, Styx(-/-) males are infertile because of structural head abnormalities in residual epididymal sperm. Immunoprecipitation of Styx with Crhsp-24, a phosphorylated RNA-binding protein implicated in translational repression of histone mRNAs, provides a strategy for regulating posttranscriptional gene expression.
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PMID:The archetype STYX/dead-phosphatase complexes with a spermatid mRNA-binding protein and is essential for normal sperm production. 1184 24

The British Andrology Workshop entitled Sperm interactions with epithelia and their products focused on the contribution of epididymal and oviductal epithelia and seminal fluid to the development of sperm function. The workshop also featured a state-of-the-art lecture entitled 'Activation of amino acid neurotransmitter receptor/chloride channels and sperm function'. Topics explored in the main body of the workshop included: the signalling pathways that might be functional in spermatozoa; whether differential subcellular localization of potential pathway components might play a role; what information could be gained from non-sperm cells; and the role of steroid hormones as potential effectors in sperm signal transduction. Tyrosine phosphorylation of downstream target proteins in spermatozoa was discussed and data were presented that supported a role for fertilization promoting peptide (FPP) in regulating sperm function in the female tract. Speakers revisited and challenged the idea that specific epididymal secretory proteins play a direct and active part in sperm functional maturation and raised the possibility that through binding and integration of DNA, spermatozoa could act as a vector for the incorporation of foreign genetic information. The roles of hyaluronic acid in maintaining sperm viability and promoting sperm capacitation and as a marker of sperm maturity were explored. Data were presented on sperm storage in birds. The workshop concluded with presentations on the potential roles of direct binding of spermatozoa to oviductal cells and their interaction with oviductal fluid components in the final preparation for successful fertilization.
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PMID:British Andrology Society Workshop: sperm interactions with epithelia and their products. 1184 73

Protein tyrosine phosphatases (PTPases) play an essential role in the regulation of steady-state phosphorylation of the insulin receptor and other proteins in the insulin signaling pathway. To determine the role of PTPases in adipose tissue in the development into an insulin-resistant state, we examined PTPase activities and protein levels of three major candidate PTPases in adipose tissues of 26-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Particulate PTPase activities in visceral and epididymal adipose tissues of OLETF rats were increased compared to those in Long-Evans Tokushima Otsuka (LETO) rats, non-insulin-resistant controls. Cytosolic PTPase activities in these tissues were conversely decreased in OLETF rats. In subcutaneous adipose tissues, those changes were not observed. Western blot analysis showed that the amounts of leukocyte antigen-related PTPase (LAR), PTPase 1B (PTP1B), and src homology 2-containing PTPase (SH-PTP2) were increased in particulate fractions of visceral and epididymal fat of OLETF rats. On the other hand, those in the cytosolic fractions were slightly decreased. Troglitazone was administered to OLETF rats to examine the effect of the drug on the changes in PTPase activity and distribution. Troglitazone treatment restored those alterations in PTPase activity in the particulate fraction and the amounts of LAR, PTP1B and SH-PTP2 in both fractions of visceral and epididymal adipose tissues of OLETF rats. Although it remains unknown whether such effects of troglitazone are mediated by peroxisome proliferator-activated receptor y, these data provide useful information for understanding the significance of PTPase in insulin-resistant rats and the molecular mechanism of troglitazone action.
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PMID:Troglitazone ameliorates abnormal activity of protein tyrosine phosphatase in adipose tissues of Otsuka Long-Evans Tokushima Fatty rats. 1236 58


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