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ABSTRACT: The blood testis barrier (BTB) is a large junctional complex composed of tight junctions, adherens junctions and gap junctions between adjacent Sertoli cells in the seminiferous tubules of the testis. Maintenance of the BTB as well as the controlled disruption and reformation of the barrier is essential for spermatogenesis and male fertility. Tyrosine phosphorylation of BTB proteins is known to regulate the integrity of adherens and tight junctions found at the BTB. SHP2 is a non-receptor protein tyrosine phosphatase (PTP) and a key regulator of growth factor-mediated tyrosine kinase signaling pathways. We found that SHP2 is localized to Sertoli-Sertoli cell junctions in rat testis. The over-expression of a constitutive active SHP2 mutant, SHP2 Q79R, up-regulated the BTB disruptor ERK1/2 via Src kinase in primary rat Sertoli cells in culture. Furthermore, focal adhesion kinase (FAK), which also supports BTB integrity, was found to interact with SHP2 and constitutive activation of SHP2 decreased FAK tyrosine phosphorylation. Expression of the SHP2 Q79R mutant in primary cultured Sertoli cells also resulted in the loss of tight junction and adherens junction integrity that corresponded with the disruption of the actin cytoskeleton and mis-localization of adherens junction and tight junction proteins N-cadherin, β-catenin and ZO-1 away from the plasma membrane. These results suggest SHP2 is a key regulator of BTB integrity and Sertoli cell support of spermatogenesis and fertility.
Biology of Reproduction 01/2013; · 4.01 Impact Factor
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ABSTRACT: The chemokine receptor CCR7 is a seven-transmembrane domain G-protein-coupled receptor that facilitates leukocyte migration to regional lymph nodes. Aberrant CCR7 expression in a number of human malignancies has been linked to pro-survival, -invasive, and -metastatic pathways. We demonstrate here that up-regulation of CCR7 in squamous cell carcinoma of the head and neck (SCCHN) patient tumors correlates with lower survival because of metastatic disease. Because of this important oncogenic phenotype, we investigated the mechanisms that regulate CCR7 expression in these tumors. Interestingly, the inflammatory transcription factor NF-κB has been associated with a more aggressive SCCHN phenotype. Immunohistochemical staining of a SCCHN tumor cohort (n = 47) strongly linked NF-κB staining and CCR7 expression in SCCHN. Thus, we investigated whether NF-κB contributes to metastatic disease by promoting CCR7 expression in SCCHN tumor cells. We characterized four novel, potential NF-κB binding sites in the 1000-bp promoter region upstream of the CCR7 gene, using luciferase, ChIP, and EMSA. However, NF-κB inhibition only resulted in partial reduction in CCR7 expression, prompting consideration of other co-regulators of CCR7. Indeed, cooperation between NF-κB and AP1 transcription factors, which are often co-activated, is crucial to the regulation of CCR7 mRNA expression in metastatic SCCHN cells. Thus, our findings support an important biological role for inflammatory NF-κB and AP1 in the regulation of CCR7 expression in metastatic SCCHN. As such, CCR7, NF-κB, and AP1 could be potentially useful therapeutic targets in controlling the progression and metastasis of SCCHN tumors.
Journal of Biological Chemistry 12/2011; 287(5):3581-90. · 4.77 Impact Factor
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ABSTRACT: Within the testis, each Sertoli cell can support a finite number of developing germ cells. During development, the cessation of Sertoli cell proliferation and the onset of differentiation establish the final number of Sertoli cells and, thus, the total number of sperm that can be produced. The upstream stimulatory factors 1 and 2 (USF1 and USF2, respectively) differentially regulate numerous Sertoli cell genes during differentiation. To identify genes that are activated by USF proteins during differentiation, studies were conducted in Sertoli cells isolated from 5- and 11-day-old rats, representing proliferating and differentiating cells, respectively. Usf1 mRNA and USF1 protein levels were increased between 5 and 11 days after birth. In vitro studies revealed that USF1 and USF2 DNA-binding activity also increased at 11 days for the promoters of four potential target genes, Fshr, Gata4, Nr5a1, and Shbg. Chromatin immunoprecipitation assays confirmed that USF recruitment increased in vivo between 5 and 11 days after birth at the Fshr, Gata4, and Nr5a1 promoters. Expression of Nr5a1 and Shbg, but not of Fshr or Gata4, mRNAs was elevated in 11-day-old Sertoli cells compared with 5-day-old Sertoli cells. Transient transfection of USF1 and USF2 expression vectors up-regulated Nr5a1 and Shbg promoter activity. RNA interference assays demonstrated that USF1 and USF2 contribute to Nr5a1 and Shbg expression in differentiating cells. Together, these data indicate that increased USF levels induce the expression of Nr5a1 and Shbg during the differentiation of Sertoli cells, whereas Fshr and Gata4 expression is not altered by USF proteins during differentiation.
Biology of Reproduction 07/2011; 85(5):965-76. · 4.01 Impact Factor
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ABSTRACT: Testosterone and FSH act in synergy to produce the factors required to maximize the production of spermatozoa and male fertility. However, the molecular mechanisms by which these hormones support spermatogenesis are not well established. Recently, we identified a nonclassical mechanism of testosterone signaling in cultured rat Sertoli cells. We found that testosterone binding to the androgen receptor recruits and activates Src tyrosine kinase. Src then causes the activation of the epidermal growth factor receptor, which results in the phosphorylation and activation of the ERK MAPK and the cAMP response element-binding protein transcription factor. In this report, we find that FSH inhibits testosterone-mediated activation of ERK and the MAPK pathway in Sertoli cells via the protein kinase A-mediated inhibition of Raf kinase. In addition, FSH, as well as inhibitors of Src and ERK kinase activity, reduced germ cell attachment to Sertoli cells in culture. Using pathway-specific androgen receptor mutants we found that the nonclassical pathway is required for testosterone-mediated increases in germ cell attachment to Sertoli cells. Studies of seminiferous tubule explants determined that Src kinase, but not ERK kinase, activity is required for the release of sperm from seminiferous tubule explants. These findings suggest the nonclassical testosterone-signaling pathway acts via Src and ERK kinases to facilitate the adhesion of immature germ cells to Sertoli cells and through Src to permit the release of mature spermatozoa. In contrast, FSH acts to limit testosterone-mediated ERK kinase activity and germ cell attachment.
Molecular Endocrinology 02/2011; 25(2):238-52. · 4.54 Impact Factor
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William H Walker
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ABSTRACT: Testosterone is essential to maintain spermatogenesis and male fertility. In the absence of testosterone stimulation, spermatogenesis does not proceed beyond the meiosis stage. After withdrawal of testosterone, germ cells that have progressed beyond meiosis detach from supporting Sertoli cells and die, whereas mature sperm cannot be released from Sertoli cells resulting in infertility. The classical mechanism of testosterone action in which testosterone activates gene transcription by causing the androgen receptor to translocate to and bind specific DNA regulatory elements does not appear to fully explain testosterone regulation of spermatogenesis. This review discusses two non-classical testosterone signalling pathways in Sertoli cells and their potential effects on spermatogenesis. Specifically, testosterone-mediated activation of phospholipase C and calcium influx into Sertoli cells is described. Also, testosterone activation of Src, EGF receptor and ERK kinases as well as the activation of the CREB transcription factor and CREB-mediated transcription is reviewed. Regulation of germ cell adhesion to Sertoli cells and release of mature sperm from Sertoli cells by kinases regulated by the non-classical testosterone pathway is discussed. The evidence accumulated suggests that classical and non-classical testosterone signalling contribute to the maintenance of spermatogenesis and male fertility.
Philosophical Transactions of The Royal Society B Biological Sciences 05/2010; 365(1546):1557-69. · 6.40 Impact Factor
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William H Walker
Endocrinology 05/2010; 151(5):1981-3. · 4.46 Impact Factor
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ABSTRACT: FSH acts through the FSH receptor (FSHR) to modulate cell processes that are required to support developing spermatozoa. Within the testis, only Sertoli cells possess receptors for FSH and are the major targets for this regulator of spermatogenesis. FSH stimulation of Sertoli cells for 24-48 h is known to induce Fshr mRNA expression through an E-box motif (CACGTG) located 25 bp upstream of the transcription start site. In contrast, FSH stimulation for 8 h inhibits Fshr transcription. DNA-protein binding studies performed using nuclear extracts from Sertoli cells show that protein binding to the Fshr promoter E-box was reduced 68% after 6 h of FSH stimulation but increased 191% over basal levels after 48 h of stimulation. The proteins binding to the Fshr E-box were identified as upstream stimulatory factor (USF)-1 and -2. FSH stimulation transiently decreased USF1 levels and increased the expression of the inhibitor of DNA binding/differentiation (ID)-2 repressor protein with the same kinetics as the decreased USF/E-box interactions. Overexpression of ID2 resulted in a dose-dependent decrease in USF-driven Fshr promoter activity in the MSC-1 Sertoli cell line, and ID2 inhibited USF binding to the Fshr E-box. Together, these studies suggest that stimulation of Sertoli cells with FSH transiently decreases expression of the USF1 activator and induces accumulation of the ID2 repressor, to block USF binding to the Fshr promoter and delay activation of Fshr transcription. This FSH-regulated mechanism may explain the cyclical changes in Fshr expression that occurs in Sertoli cells in vivo.
Endocrinology 06/2009; 150(8):3783-91. · 4.46 Impact Factor
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ABSTRACT: Restitution kinetics (RK) of action potential duration (APD) are classically studied by applying an extra impulse at varying diastolic intervals (DI) and might differ from RK elicited by sympathetic nerve stimulation (SNRK).
To measure 'Physiological' RK during gradual increases in heart rate caused by sympathetic nerve stimulation (SNS) and its possible spatial heterogeneities caused by non-uniform innervation of the myocardium.
The SNRK was measured from rabbit hearts with intact sympathetic innervation using optical mapping. APD versus DI were plotted from left ventricles during SNS, then with pacing using identical activation interval (AI) sequences.
AI decreased (444 +/- 18 ms to 284 +/- 9 ms) in 25 s and recovered to baseline on SNS suspension (n = 10). APD versus DI plots were identical for SNS and pacing except that when maximum heart rate was reached, SNS elicited a further APD shortening compared with pacing. During SNS, APDs decreased from 216 +/- 9 ms to 154 +/- 7 ms (29% +/- 2%) at the base and from 206 +/- 12 ms to 158 +/- 7 ms (20% +/- 2%) at the apex. During pacing, APDs at the base decreased from 216 +/- 9 ms to 170 +/- 7 ms (21% +/- 1%, SNS versus pacing: P < .05). In contrast, RK were similar at the apex for SNS and pacing. During SNS, the extra APD shortening at the base was associated with longer segments of RK curves with negative slopes and extra DI prolongation. Perfusion with the I(Ks) inhibitor HMR 1556 (0.5 microM; n = 5) abolished differences in RK between SNS and pacing. Levels of KCNQ1 and tyrosine hydroxylase proteins were greater at the base than apex (n = 4), implying that apex-base distributions for I(Ks) and sympathetic innervation are congruent with SNRK heterogeneities.
The findings shed further insights on heterogeneities of sympathetic nerves, RK, and the role of I(Ks) in cardiac repolarization.
Heart rhythm: the official journal of the Heart Rhythm Society 06/2009; 6(5):696-706. · 4.56 Impact Factor
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ABSTRACT: Each Sertoli cell can support a finite number of developing germ cells. During development of the testis, the cessation of Sertoli cell proliferation and the onset of differentiation determine the final number of Sertoli cells and, hence, the number of sperm that can be produced. We hypothesize that the transition from proliferation to differentiation is facilitated by E-box transcription factors that induce the expression of differentiation-promoting genes. The relative activities of E-box proteins were studied in primary Sertoli cells isolated from 5-, 11-, and 20-day-old rats, representing proliferating, differentiating, and differentiated cells, respectively. E-box DNA-binding activity is almost undetectable 5 days after birth but peaks with initiation of differentiation 11 days after birth and remains elevated. Upstream stimulatory factors 1 and 2 (USF1 and USF2) were found to be the predominant E-box proteins present within DNA-protein complexes formed after incubating E-box-containing probes with nuclear extracts from developing Sertoli cells. The known potentiator of Sertoli cell differentiation, thyroxine, increases USF DNA-binding activity in Sertoli cells before differentiation (5-day-old Sertoli cells) but not after differentiation is initiated (11- and 20-day-old Sertoli cells). The developmental-specific increase in USF1 and USF2 DNA-binding activity may facilitate the switch from proliferation to differentiation and, thus, determine the ultimate number of Sertoli cells present within the testes and the upper limit of fertility.
Biology of Reproduction 10/2008; 80(1):24-33. · 4.01 Impact Factor
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ABSTRACT: Increased distal nephron sodium absorption in response to aldosterone involves Nedd4-2 phosphorylation, which blocks its ability to ubiquitylate ENaC and increases apical membrane channel density by reducing its endocytosis. Our prior work (Liang, X., Peters, K. W., Butterworth, M. B., and Frizzell, R. A. (2006) J. Biol. Chem. 281, 16323-16332) showed that aldosterone selectively increased 14-3-3 protein isoform expression and that the association of 14-3-3beta with phospho-Nedd4-2 was required for sodium transport stimulation. The knockdown of 14-3-3beta alone nearly eliminated the response to aldosterone, despite the expression of other 14-3-3 isoforms in cortical collecting duct (CCD) cells. To further examine this marked effect of 14-3-3beta knockdown, we evaluated the hypothesis that phospho-Nedd4-2 binding prefers a heterodimer composed of two different 14-3-3 isoforms. We tested this concept in polarized CCD cells using RNA interference and assays of sodium transport and of the interaction of Nedd4-2 with 14-3-3epsilon, a second aldosterone-induced isoform. As observed previously for 14-3-3beta knockdown, small interfering RNA-induced reduction of 14-3-3epsilon markedly attenuated aldosterone-stimulated ENaC expression and sodium transport and increased the interaction of Nedd4-2 with ENaC toward prealdosterone levels. After aldosterone induction, 14-3-3beta and 14-3-3epsilon were quantitatively co-immunoprecipitated from CCD cell lysates, and the association of both isoforms with Nedd4-2 increased. Finally, the knockdown of either 14-3-3beta or 14-3-3epsilon reduced the association of Nedd4-2 with the other isoform. We conclude that the two aldosterone-induced 14-3-3 isoforms, beta and epsilon, interact with phospho-Nedd4-2 as an obligatory heterodimer, blocking its interaction with ENaC and thereby increasing apical ENaC density and sodium transport.
Journal of Biological Chemistry 09/2008; 283(41):27418-25. · 4.77 Impact Factor
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ABSTRACT: In congenital and acquired long QT type 2, women are more vulnerable than men to torsade de pointes. In prepubertal rabbits (and children), the arrhythmia phenotype is reversed; however, females still have longer action potential durations than males. Thus, sex differences in K(+) channels and action potential durations alone cannot account for sex-dependent arrhythmia phenotypes. The L-type calcium current (I(Ca,L)) is another determinant of action potential duration, Ca(2+) overload, early afterdepolarizations (EADs), and torsade de pointes. Therefore, sex, age, and regional differences in I(Ca,L) density and in EAD susceptibility were analyzed in epicardial left ventricular myocytes isolated from the apex and base of prepubertal and adult rabbit hearts. In prepubertal rabbits, peak I(Ca,L) at the base was 22% higher in males than females (6.4+/-0.5 versus 5.0+/-0.2 pA/pF; P<0.03) and higher than at the apex (6.4+/-0.5 versus 5.0+/-0.3 pA/pF; P<0.02). Sex differences were reversed in adults: I(Ca,L) at the base was 32% higher in females than males (9.5+/-0.7 versus 6.4+/-0.6 pA/pF; P<0.002) and 28% higher than the apex (9.5+/-0.7 versus 6.9+/-0.5 pA/pF; P<0.01). Apex-base differences in I(Ca,L) were not significant in adult male and prepubertal female hearts. Western blot analysis showed that Ca(v)1.2alpha levels varied with sex, maturity, and apex-base, with differences similar to variations in I(Ca,L); optical mapping revealed that the earliest EADs fired at the base. Single myocyte experiments and Luo-Rudy simulations concur that I(Ca,L) elevation promotes EADs and is an important determinant of long QT type 2 arrhythmia phenotype, most likely by reducing repolarization reserve and by enhancing Ca(2+) overload and the propensity for I(Ca,L) reactivation.
Circulation Research 05/2008; 102(9):e86-100. · 9.49 Impact Factor
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ABSTRACT: A new pathway of testosterone (T) action in Sertoli cells was recently identified that may be required to support spermatozoa production (spermatogenesis) and fertility. Specifically, T acts via the androgen receptor (AR) to rapidly activate the MAPK cascade and the cAMP response element-binding protein (CREB) transcription factor in Sertoli cells. In further characterizing the signaling pathway that transduces T actions, we now find that a population of AR is localized to the plasma membrane and that AR associates with Src kinase after T stimulation. In addition, we demonstrate that Src kinase is activated by T and that Src kinase activity is required for stimulation of the ERK MAPK and CREB. Furthermore, we determine that activation of the epidermal growth factor receptor downstream of Src contributes to the activation of the MAPK cascade and CREB. The elucidation of this nonclassical pathway of T action in the testis may provide new targets for the control of male fertility.
Endocrinology 06/2007; 148(5):2066-74. · 4.46 Impact Factor
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ABSTRACT: Chemokine receptor 7 (CCR7) mediates leukocyte adhesion and chemotaxis from peripheral sites of inflammation through lymphatic channels to secondary lymphoid organs. Aberrant CCR7 expression has been identified on certain tumor types and been linked to pro-survival and invasive pathways. In metastatic squamous cell carcinoma of the head and neck (SCCHN), we have described the selective upregulation of functional CCR7. In this manuscript, we review our understanding of CCR7-mediated signaling in metastatic SCCHN and provide evidence for its involvement in tumor survival, invasion, and metastasis. Autocrine and paracrine CCR7 activation appears to propagate the response to the CCR7 ligands CCL19 and CCL21, which are expressed by the lymphatic endothelium, secondary lymphoid tissues, and CCR7-positive tumor cells. Based on our recent findings, the induction of CCR7 expression and the sustenance of the autocrine signaling pathway have been shown to be regulated by NF-kappaB, similar to several types of immune cells. While extending these observations to metastatic SCCHN tumor cells, our studies highlight the importance of downstream NF-kappaB mediated CCR7 signals in the progression of SCCHN malignancy.
Immunologic Research 02/2006; 36(1-3):61-72. · 3.03 Impact Factor
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ABSTRACT: Testosterone and follicle-stimulating hormone (FSH) are required to obtain full reproductive potential. In the testis, somatic Sertoli cells transduce signals from testosterone and FSH into the production of factors that are required by germ cells as they mature into spermatozoa. Recent advances in identifying new signaling pathways that are regulated by FSH and testosterone have allowed for refinement in the understanding of the independent, overlapping and synergistic actions of these hormones. In this review, we discuss the signaling pathways that are regulated by FSH and testosterone as well as the resulting metabolic and gene expression changes that occur as related to Sertoli cell proliferation, differentiation and the support of spermatogenesis.
Reproduction (Cambridge, England) 08/2005; 130(1):15-28. · 3.09 Impact Factor
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ABSTRACT: The androgen testosterone is essential for the Sertoli cell to support the maturation of male germ cells and the production of spermatozoa (spermatogenesis). In the classical view of androgen action, binding of androgen to the intracellular androgen receptor (AR) produces a conformational change in AR such that the receptor-steroid complex has high affinity for specific DNA regulatory elements and is able to stimulate gene transcription. Here, we demonstrate that testosterone can act by means of an alternative, rapid, and sustainable mechanism in Sertoli cells that is independent of AR-DNA interactions. Specifically, the addition of physiological levels of testosterone to Sertoli cells stimulates the mitogen-activated protein kinase signaling pathway and causes phosphorylation of the cAMP response element binding protein transcription factor on serine 133, a modification known to be required for Sertoli cells to support spermatogenesis. Androgen-mediated activation of mitogen-activated protein kinase and cAMP response element binding protein occurs within 1 min, extends for at least 12 h and requires AR. Furthermore, androgen induces endogenous cAMP response element binding protein-mediated transcription in Sertoli cells. These newly identified mechanisms of androgen action in Sertoli cells suggest new targets for developing male contraceptive agents.
Proceedings of the National Academy of Sciences 08/2004; 101(30):10919-24. · 9.68 Impact Factor
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ABSTRACT: The cyclic AMP response element (CRE) has been implicated in the regulation of the expression of many genes and cellular processes important in hepatocyte function. CRE sites exist in the promoter regions of several genes expressed during inflammation. Numerous studies on the role of CRE in hepatocyte gene expression have been performed in resting hepatocytes, but the role of CRE during inflammation is unknown. To evaluate the regulation of CRE-mediated transcription during sepsis, cultured hepatocytes were exposed to proinflammatory cytokines and lipopolysaccharide (LPS) was injected into rats. Nuclear proteins were collected and CRE binding activity measured by electromobility shift assay (EMSA) using a consensus CRE oligonucleotide. CRE binding activity was increased in vitro by cytokines and in vivo by LPS administration but CRE-dependent reporter activity was decreased by cytokine stimulation. A c-jun N-terminal kinase (JNK) inhibitor reversed the cytokine-induced increase in CRE binding and increased CRE-dependent reporter activity. Supershift assays indicated that cyclic AMP response element binding protein (CREB) and c-Jun proteins were included in the CRE binding complex. CREB induced and c-Jun suppressed reporter activity using a CRE-dependent construct transfected into cultured primary hepatocytes. In conclusion, these data demonstrate that proinflammatory cytokines regulate CRE binding and activity in cultured hepatocytes and suggest that sepsis-induced changes in CRE binding may participate in the cellular response to inflammation.
Hepatology 06/2004; 39(5):1343-52. · 11.66 Impact Factor
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ABSTRACT: Id (inhibitor of DNA binding/differentiation) proteins repress differentiation and promote cell division by dimerizing with and inhibiting the action of basic helix-loop-helix transcription factors including those that bind to E-box motifs. Of the four characterized Id proteins, only Id2 is found in the nucleus of Sertoli cells that support the development of spermatozoa in the testis. Differential display analysis of rat primary Sertoli cell mRNA identified Id2 as being inducible by forskolin, a stimulator of cAMP production. Northern blot analysis confirmed that Id2 mRNA expression peaked in Sertoli cells 6-12 h after stimulation with forskolin or follicle-stimulating hormone (FSH), the major physiological stimulator of cAMP in Sertoli cells. Similarly, Id2 promoter activity in Sertoli cells was induced after forskolin or FSH stimulation as well as by overexpression of protein kinase A. Forskolin induction of the Id2 promoter required sequences located between positions -122 and -82. Protein(s) of 40-45 kDa were found to bind two activated transcription factor/cAMP-response element-like sites and a GATA motif within the regulatory region. The induction of the Id2 gene by FSH corresponded with a decrease in protein binding to an E-box consensus motif and decreased E-box-mediated transcription. Together, these findings raise the possibility that FSH-mediated induction of Id2 and resultant inhibition of basic helix-loop-helix transcription factor-regulated genes in Sertoli cells may contribute to the regulation of spermatogenesis.
Journal of Biological Chemistry 05/2004; 279(16):16064-70. · 4.77 Impact Factor
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William H Walker
Endocrinology 10/2003; 144(9):3719-21. · 4.46 Impact Factor
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ABSTRACT: Germ cell development within the mammalian testis requires testosterone stimulation of somatic Sertoli cells via interaction with intracellular androgen receptors (AR). AR expression levels undergo marked changes during spermatogenesis suggesting that the modulation of AR expression is an important mechanism to regulate Sertoli cell responsiveness to testosterone. An analysis of the AR gene promoter revealed three kappaB enhancer elements that interacted with Sertoli cell p50 and RelA NF-kappaB proteins, and the overexpression of these NF-kappaB subunits in Sertoli cells stimulated AR promoter activity. Moreover, TNF-alpha, a secretory product of round spermatids, stimulated NF-kappaB binding to the AR promoter, induced AR promoter activity, and increased endogenous AR expression in primary cultures of Sertoli cells. Given the requirement of testosterone for spermatogenesis and the importance of AR in mediating Sertoli cell responsiveness to testosterone, the stimulation of AR expression by NF-kappaB and TNF-alpha may represent an important regulatory mechanism required to maintain efficient spermatogenesis.
Molecular and Cellular Endocrinology 04/2003; 201(1-2):1-12. · 4.19 Impact Factor
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William H Walker
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ABSTRACT: Nongenomic actions mediated by androgens have now been described in more than 10 cell types. Some of these cells transduce androgen signals using surface receptors that await final characterization, whereas other cells employ the classical AR. Various second messengers can be activated by androgens, including cAMP, IP3, phospholipase C, DAG, and Ca2+. Each of these second messengers is capable of activating multiple kinases. One of the most important kinase networks to be regulated by androgens is the MAP kinase cascade. This series of kinase reactions is capable of altering the activity of many transcription factors with important implications for the regulation of gene expression. Because there is evidence that androgen is capable of regulating CREB-mediated gene expression via the MAP kinase pathway, it is now somewhat misleading to characterize androgen actions in Sertoli cells as nongenomic. Instead, it may be more appropriate to label these activities as independent of AR-DNA interactions, or more simply as nonclassical. The nonclassical regulation of gene expression in Sertoli cells is particularly relevant for providing an answer to the paradox of how testosterone can support spermatogenesis yet regulate few genes via AR-promoter interactions. It is expected that with the increasing use of microarray and related technologies, additional AR-regulated genes will be identified. However, the androgen-induced increases in [Ca2+]i, the activation of Src kinase, and the MAP kinase cascade that have been characterized thus far have the potential to regulate the expression of many more genes than is possible by direct AR-promoter interactions. Thus, it is likely that nonclassical actions of testosterone in Sertoli cells will be found to be a necessary complement to the classical actions that are required to maintain spermatogenesis.
Current Topics in Developmental Biology 02/2003; 56:25-53. · 6.00 Impact Factor
