Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ethane dimethanesulphonate (EDS) is cytotoxic to Leydig cells in the adult rat. To investigate the role and regulation of apoptosis in the Leydig cell, EDS (100 mg/kg i.p.) was administered to adult male rats and the testes examined 6, 12, 18, 24, 48 and 72 h later. Numbers of Leydig cells, identified by 3 beta-hydroxysteroid dehydrogenase immuno-histochemistry started to fall by 12 h after EDS injection and were almost undetectable by 72 h. Apoptotic cells in the interstitium, visualised by in situ end labelling of DNA, increased in number to reach a maximum 24 h after injection of EDS, and were undetectable by 72 h. In many tissues the apoptosis-related gene products act in cohort: Bcl-2 and Bcl-xl promoting survival of a cell, whilst Bax promotes cell death often positively regulated by the tumour-suppressor gene p53. Western blot analysis showed that: (1) Bcl-2 and p53 were absent from interstitial Leydig cells but were expressed in the seminiferous tubules. (2) Bax protein although expressed in the interstitium was not present in the Leydig cells. (3) Bcl-xl in Leydig cells was transiently increased after EDS. In conclusion, EDS kills Leydig cells by apoptosis; however the control of Leydig cell death does not involve p53 or the Bcl-2 family members but may require other gene products yet to be identified.
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PMID:Leydig cell apoptosis in the rat testes after administration of the cytotoxin ethane dimethanesulphonate: role of the Bcl-2 family members. 965 95

Programmed cell death is an important regulatory event in spermatogenesis. However, the molecular events governing apoptosis have not been characterized. Using the Leydig cell-specific toxin ethane dimethanesulfonate (EDS) to withdraw androgen support, we have investigated the relationship between apoptosis and apoptosis-related genes. Adult male Sprague-Dawley rats were injected (i.p.) with 100 mg/kg EDS and killed at times of androgen depletion 2, 5, and 8 days postinjection. A 24-fold increase in the apoptotic index 8 days after EDS administration was demonstrated in tissue sections by in situ end-labeling of fragmented DNA. Leydig cell death and androgen withdrawal were confirmed by the absence of 3beta-hydroxysteroid dehydrogenase in testes from animals treated with EDS for 2 days. After androgen withdrawal, there were no significant changes in the levels of clusterin, Bcl-xl, Bak, and Bad. However, the expression of Bcl-2 and Bax was up-regulated at 8 days after EDS administration. The induction of Bax at this time suggests that it may play a role in germ cell apoptosis following androgen withdrawal. The concomitant elevation in Bcl-2 expression may represent a survival mechanism for the remaining germ cells. There was also a decline in the expression of Fas-L and Fas-R in the pachytene spermatocytes and spermatids. Fas-R was also present in Sertoli cells, although Fas-L staining was minimal. As the colocalization of Fas-L and Fas-R correlates with the germ cell types that die in response to androgen withdrawal, the potential exists for apoptosis in the rat spermatogenic epithelium to be regulated by the Fas pathway.
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PMID:Apoptosis in the rat spermatogenic epithelium following androgen withdrawal: changes in apoptosis-related genes. 991 15

Leydig cells undergo apoptosis in response to the cytotoxin ethane dimethanesulfonate (EDS), with numbers declining at 12-18 h and maximal apoptosis at 24 h postinjection. The Bcl-2 family members, Bcl-2, Bcl-xl, and Bax, appear not to be involved in this process. To further investigate this phenomena, a single dose of EDS was administered to adult rats to induce the killing of Leydig cells. The interstitial cells were examined up to 3 days after EDS administration by Western blot analysis for the Bcl-2 family members (Bak and Bcl-w). Western blotting showed that Bak expression in the interstitial cell preparations was unchanged after EDS, and immunohistochemistry showed that it was not up-regulated in Leydig cells in response to EDS. Bcl-w expression in the Leydig cells and interstitial cell preparations was unchanged until 48 h when it became undetectable, suggesting that Leydig cell-associated Bcl-w is not involved in initiating apoptosis. We also investigated the role of the Fas system in Leydig cell apoptosis. Both Fas receptor and Fas ligand protein levels increased after EDS, peaking at 12-18 h and declining thereafter. Fas receptor and ligand were shown by immunohistochemistry to be present in Leydig cells, and after EDS all Leydig cells became strongly positive for both proteins. The intensity of staining increased in the early stages of apoptosis and decreased as the nuclear morphology became more fragmented. These data suggest that Bcl-2 family members are not involved in Leydig cell apoptosis after EDS administration. However, up-regulation of the Fas system does occur, implicating activation of Fas receptor in the induction of Leydig cell apoptosis.
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PMID:Leydig cell apoptosis after the administration of ethane dimethanesulfonate to the adult male rat is a Fas-mediated process. 1043 41

Androgen secreting Leydig cells in the adult are differentiated with a very low turnover, however, Leydig cell tumours can arise spontaneously or after treatment with toxins. This study in the rat investigated whether changes in components of programmed cell death could be involved. In contrast to their absence in differentiated Leydig cells, antiapoptotic Bcl-2 and proapoptotic Bax were expressed in tumours. Bak and Bcl-xl were found in both tumour and normal Leydig cells. Apoptosis was induced in subcutaneous implants of Leydig cell tumour by ethane dimethanesulphonate (EDS) which is known to kill differentiated Leydig cells. The marked regression of the tumour following EDS treatment was transient and re-growth occurred between 6 and 14 days later. Tumour regression and growth was associated with a similar weight pattern in the seminal vesicles caused by changes in serum testosterone. During tumour regression, clusterin and Bax proteins were elevated but Bak, Bcl-xl and Bcl-2 were unchanged. Fas-R, Fas-L and Bax were upregulated after tumour regression had taken place. These data show that Leydig cell tumours possess many of the apoptosis related gene products and can die by apoptosis, however, regulation is clearly different in differentiated and mitotic Leydig cells.
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PMID:Apoptosis related gene products in differentiated and tumorigenic rat Leydig cells and following regression induced by the cytotoxin ethane dimethanesulphonate. 1116 51

To explore the functional role of Bcl-2 in germ cell development, transgenic mice carrying 6 kilobases of the inhibin-alpha promoter were generated to express human bcl-2 gene product in the gonads. Although female transgenic mice demonstrated decreased follicle apoptosis, enhanced folliculogenesis, and increased germ cell tumorigenesis, the adult males exhibited variable impairment of spermatogenesis. The degree of damage ranged from tubules with intraepithelial vacuoles of varying sizes to near atrophied tubules consisting of Sertoli cells and a few spermatogonia. Although there was no significant change in body weight, an approximately 34% decrease in testicular weights was noted in transgenic animals compared with wild-type mice. Gamete maturation, assessed by determining the percentage of tubules with advanced (steps 13-16) spermatids, was decreased to 44.4% of the values measured in the wild-type animals. The incidence of germ cell apoptosis increased 3.8-fold in the transgenic animals and was associated with a marked loss of germ cells. Electron microscopy of the testes further revealed large vacuoles in the Sertoli cell cytoplasm and dilations of the intracellular spaces between adjacent Sertoli cells, spermatid malformations, and increased germ cell apoptosis in the transgenic animals. There was no evidence of Sertoli cell death either by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay or electron microscopy. Leydig cell ultrastructure, cell size and numbers, and plasma levels of testosterone were not different between normal and the transgenic animals. Collectively, these results support the critical role of Bcl-2 in male germ cell development and are consistent with the gender-specific role of the Bcl-2 family members in reproduction.
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PMID:Impairment of spermatogenesis in transgenic mice with selective overexpression of Bcl-2 in the somatic cells of the testis. 1170 Aug 63

Apoptosis is necessary for the development and maturation of Leydig cells. However, increased apoptosis results the decline of testosterone production, which may increase germ cell apoptosis and the possibility of infertility. There are several aspects contributing to Leydig cell apoptosis such as ethane dimethanesulphonate (EDS), glucocorticoid, developmental stage and some hormones including FSH, LH/hCG and testosterone. A number of genes are involved in the regulation of Leydig cells apoptosis. It was reported that SCF/c-kit, Bcl-2 and Bcl-xl inhibited the apoptosis while caspase-3, Fas, Bax and clusterine stimulated it.
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PMID:[Leydig cell apoptosis and its regulation]. 1286 41

The present investigation examines the influence of IGF-I and the role of IGF-I receptor (IGF-IR) in the apoptosis/survival of Leydig cells. Immunohistochemical analysis of the rat testis at different ages revealed that the level of the phosphorylated IGF-IR increases from birth to d 20 of postnatal life, remaining high in the adult testis. Western blotting revealed that this level is higher in Leydig cells isolated from 40-d-old than from 10- or 60-d-old rats. Application of the terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay revealed that IGF-I decreases the level of apoptosis in Leydig cells at all stages of development, and the selective inhibitor of IGF-IR, picropodophyllin, blocks this antiapoptotic effect. The mechanism underlying the antiapoptotic action of IGF-I involves the phosphatidylinositol 3-kinase/Akt pathway, and in immature Leydig cells, this growth factor enhances the expression of Bcl-2 and cellular inhibitor of apoptosis proteins 2, while preventing activation of caspase-3 by cleavage. Furthermore, IGF-II and high concentrations of insulin also evoke phosphorylation of IGF-IR and, like IGF-I, enhance the expression of the steroidogenic acute regulatory protein by Leydig cells. Inhibition of IGF-IR by picropodophyllin decreases the survival of Leydig cells, both in the presence and absence of IGF-I, demonstrating that signaling via the IGF-IR plays an important role in Leydig cell survival.
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PMID:Insulin-like growth factor-I is an important antiapoptotic factor for rat leydig cells during postnatal development. 1702 32

Epidemiological and experimental studies have shown that cadmium is carcinogenic to human and experimental animals, however, the mechanism of cadmium-induced carcinogenesis is not clear. The aberrant expression of cell cycle and DNA repair genes resulting in increased cell proliferation and genomic instability are the characteristic features of cancer cells. The purpose of this study was to determine if exposure to cadmium can perturb cell proliferation/survival and causes genomic instability in TM3 cells, a mouse testicular Leydig cell line. The results of this study revealed that short-duration exposure to lower doses of cadmium significantly increase the growth of TM3 cells, whereas, higher doses are toxic and cause cell death. The long duration exposure to higher doses of cadmium, however, results in increased cell survival and acquisition of apoptotic resistance. Gene expression analysis by real-time PCR revealed increased expression of the anti-apoptotic gene Bcl-2, whereas decreased expression of pro-apoptotic gene Bax. Decreased expression of genes for maintenance of DNA methylation, DNMT1, and DNA repair, OGG1 and MYH, was also observed in cells exposed to cadmium for 24h. The random amplified polymorphic DNA (RAPD) assay revealed genomic instability in cells with chronic exposure to cadmium. The findings of this study indicate that mouse testicular Leydig cells adapt to chronic cadmium exposure by increasing cell survival through increased expression of Bcl-2, and decreased expression of Bax. The increased proliferation of cells with genomic instability may result in malignant transformation, and therefore, could be a viable mechanism for cadmium-induced cancers.
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PMID:Long duration exposure to cadmium leads to increased cell survival, decreased DNA repair capacity, and genomic instability in mouse testicular Leydig cells. 1923 59

Several reports indicate that transforming growth factor beta1 (TGF-beta1) participates in the regulation of cell cycle progression. In this work, we analyzed the in vitro effect of TGF-beta1 on Leydig cell proliferation markers and the in vivo effect of this cytokine in Leydig cell hyperplasia/hypertrophy. The in vitro effect of TGF-beta1 (1 ng/ml) plus progesterone (10(-6) M) on purified Leydig cells from 3 week-old mice increased the immunocytochemically detected PCNA and stimulated the phosphorylation of Smad 1/5. Progesterone (10(-6) M) in the presence or absence of TGF-beta1 diminished the ratio Bax/Bcl-2. Morphometric testicular studies of mice treated with progesterone (s.c.) plus TGF-beta1 (intratesticular), showed an increase in interstitial volume and a decrease in tubular volume. Furthermore, the cytoplasmic volume of Leydig cells showed an increment in this experimental group with a diminution in nuclear volume. Thus, it turned out that the administration of progesterone and TGF-beta1 augmented the volume of Leydig cells. These results indicate a clear effect of TGF-beta1 in the hypertrophy/hyperplasia of Leydig cells.
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PMID:TGF-beta1 system in Leydig cells. Part II: TGF-beta1 and progesterone, through Smad1/5, are involved in the hyperplasia/hypertrophy of Leydig cells. 2043 Dec 51

We have earlier reported that following persistent stimulation with hCG, oxidative stress-induced apoptosis in rat Leydig cells was mainly achieved through the extrinsic pathway. In the present study, the role of N-acetylcysteine (NAC) in counteracting the oxidative stress and the mechanisms of inhibition of apoptosis under such conditions were investigated. NAC (1 mM) intervention with repeated hCG stimulation (50 ng/ml, four times, each with 30 min challenge) prevented the decline in Leydig cell viability and the rise in lipid peroxidation and reactive oxygen species. Simultaneously, the activities of the enzymes glutathione-S-transferase, catalase, superoxide dismutase and the intracellular glutathione and antioxidant capacity of the treated cells improved significantly. Apoptotic markers Fas, FasL, and caspase-8, up-regulated following repeated hCG exposure, were significantly down-regulated following NAC co-incubation. While Bcl-2 expression was fully restored, Bax and caspase-9 remained unchanged. NAC treatment induced down-regulation of upstream JNK/pJNK and down-stream caspase-3 in the target cells. Taken together, the above findings indicate that NAC counteracted the oxidative stress in Leydig cells induced as a result of repeated hCG stimulation, and inhibited apoptosis by mainly regulating the extrinsic and JNK pathways of metazoan apoptosis.
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PMID:N-acetylcysteine counteracts oxidative stress and prevents hCG-induced apoptosis in rat Leydig cells through down regulation of caspase-8 and JNK. 2082 44


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