Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of regucalcin, a regulatory protein in intracellular signaling pathway, in cell death was investigated by using the cloned rat hepatoma H4-II-E cells overexpressing regucalcin. The hepatoma cells (wild-type) and stable regucalcin/pCXN2 transfectants were cultured for 72 h in a medium containing 10% fetal bovine serum (FBS) to obtain subconfluent monolayers. After culture for 72 h, cells were further cultured for 24-72 h in a medium containing either vehicle, insulin (10(-8) or 10(-7) M) or insulin-like growth factor-I (IGF-I; 10(-9) or 10(-8) M) in the absence of FBS. The number of wild-type cells was significantly decreased by culture for 24, 48, or 72 h in the presence of insulin (10(-8) or 10(-7) M) or IGF-I (10(-9) or 10(-8) M). Agarose gel electrophoresis showed the presence of low-molecular-weight deoxyribonucleic acid (DNA) fragments of adherent wild-type cells cultured with insulin or IGF-I. The effect of insulin or IGF-I in stimulating cell death and DNA fragmentation in hepatoma cells (wild-type) was significantly prevented in transfectants overexpressing regucalcin. Meanwhile, epinephrine (10(-6) or 10(-5) M) or transforming growth factor-beta1 (10(-13) or 10(-12) M) did not cause cell death of hepatoma cells. Insulin-induced decrease in the number of wild-type cells was significantly prevented by culture with caspase-3 inhibitor (10(-8) M), although the effect of IGF-I was not inhibited. The effect of insulin or IGF-I in inducing the death of hepatoma cells (wild-type) was significantly prevented in the presence of N omega-nitro-L-arginine methylester (NAME), an inhibitor of nitric oxide synthase. Genistein (10(-6) M), an inhibitor of protein tyrosine kinase, or vanadate (10(-5) M), an inhibitor of protein tyrosine phosphatase, caused a significant decrease in the number of hepatoma cells (wild-type). The effect of insulin in inducing the death of wild-type cells was not seen in the presence of genistein or vanadate. The effect of IGF-I on the death of wild-type cells was observed in the presence of genistein or vanadate. The effect of genistein on cell death was significantly prevented in transfectants. Such effect was not seen with vanadate. This study demonstrates that insulin or IGF-I stimulates cell death and apoptosis in the hepatoma cells, and that overexpression of regucalcin has a suppressive effect on cell death induced by insulin or IGF-I that is mediated through different signaling pathway.
 ...
PMID:Overexpression of regucalcin suppresses cell death and apoptosis in cloned rat hepatoma H4-II-E cells induced by insulin or insulin-like growth factor-I. 1588 Jun 94

We have demonstrated that insulin-like growth factor binding protein-5 (IGFBP-5) production by mammary epithelial cells increases dramatically during forced involution of the mammary gland in rats, mice and pigs. We proposed that growth hormone (GH) increases the survival factor IGF-I, whilst prolactin (PRL) enhances the effects of GH by decreasing the concentration of IGFBP-5, which would otherwise inhibit the actions of IGFs. To demonstrate a causal relationship between IGFBP-5 and cell death, we created transgenic mice expressing IGFBP-5, specifically, in the mammary gland. DNA content in the mammary glands of transgenic mice was decreased as early as day 10 of pregnancy. Mammary cell number and milk synthesis were both decreased by approximately 50% during the first 10 days of lactation. The concentrations of the pro-apoptotic molecule caspase-3 was increased in transgenic animals whilst the concentrations of two pro-survival molecules Bcl-2 and Bcl-x were both decreased. In order to examine whether IGFBP-5 acts by inhibiting the survival effect of IGF-I, we examined IGF receptor- and Akt-phoshorylation and showed that both were inhibited. These studies also indicated that the effects of IGFBP-5 could be mediated in part by IGF-independent effects involving potential interactions with components of the extracellular matrix involved in tissue remodeling, such as components of the plasminogen system, and the matrix metallo-proteinases (MMPs). Mammary development was normalised in transgenic mice by R3-IGF-I, an analogue of IGF-I which binds weakly to IGFBPs, although milk production was only partially restored. In contrast, treatment with prolactin was able to inhibit early involutionary processes in normal mice but was unable to prevent this in mice over-expressing IGFBP-5, although it was able to inhibit activation of MMPs. Thus, IGFBP-5 can simultaneously inhibit IGF action and activate the plasminogen system thereby coordinating cell death and tissue remodeling processes. The ability to separate these properties, using mutant IGFBPs, is currently under investigation.
 ...
PMID:Insulin-like growth factor binding proteins initiate cell death and extracellular matrix remodeling in the mammary gland. 1599 1

Transgenic mice expressing IGFBP-5 in the mammary gland exhibit increased cell death and plasmin generation. Because IGFBP-5 has been reported to bind to plasminogen activator inhibitor-1 (PAI-1), we determined the effects of this interaction in HC11 cells. PAI-1 prevented plasmin generation from plasminogen and inhibited cleavage of focal adhesions, expression of caspase 3, and cell death. IGFBP-5 could in turn prevent the effects of PAI-1. IGFBP-5 mutants with reduced affinity for IGF-I (N-term) or deficient in heparin binding (HEP- and C-term E and F) were also effective. This was surprising because IGFBP-5 reportedly interacts with PAI-1 via its heparin-binding domain. Biosensor analysis confirmed that, although wild-type IGFBP-5 and N-term both bound to PAI-1, the C-term E had greatly decreased interaction with PAI-1. This suggests that IGFBP-5 does not antagonize the actions of PAI-1 by a direct molecular interaction. In a cell-free system, using tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) to activate plasminogen, PAI-1 inhibited plasmin generation induced by both activators, whereas IGFBP-5 prevented the effects of PAI-1 on tPA but not uPA. Furthermore, we noted that IGFBP-5 activated plasminogen to a greater extent than could be explained solely by inhibition of PAI-1, suggesting that IGFBP-5 could directly activate tPA. Indeed, IGFBP-5 and the C-term E and F were all able to enhance the activity of tPA but not uPA. These data demonstrate that IGFBP-5 can enhance the activity of tPA and that this can result in cell death induced by cleavage of focal adhesions. Thus IGFBP-5 can induce cell death by both sequestering IGF-I and enhancing plasmin generation.
 ...
PMID:Insulin-like growth factor-binding protein-5 activates plasminogen by interaction with tissue plasminogen activator, independently of its ability to bind to plasminogen activator inhibitor-1, insulin-like growth factor-I, or heparin. 1650 91

Diabetic retinopathy can result in apoptotic cell death of retinal neurons, as well as significant visual loss. It is further known that insulin-like growth factor (IGF) levels are reduced in diabetes and that IGF-I can prevent cell death in many cell types. In this study, we tested the hypothesis that systemic treatment with IGF-I could inhibit death of neuroretinal cells in diabetic rats by examining the expression of proapoptotic markers. In diabetic rat retina, the number of TUNEL-immunoreactive cells increased approximately sixfold in the photoreceptor layer (P<.001) and eightfold in the inner nuclear layer (INL; P<.001); phospho-Akt (p-Akt; Thr 308) immunoreactivity increased eightfold in the ganglion cell layer (GCL; P<.001) and threefold in the INL (P<.01). Subcutaneous IGF-I treatment significantly reduced the number of TUNEL (P<.001) and p-Akt immunoreactive retinal cells (P<.05) in diabetic rats approximately to the level of the nondiabetic group. Qualitative results showed that caspase-3 and BAD immunoreactivities were also elevated in diabetes and reduced in IGF-I-treated animals. Elevated TUNEL and p-Akt immunoreactivities were localized to distinct cell layers in the retina of diabetic rats. Early intervention with systemic IGF-I reduced the presence of proapoptotic markers indicative of neuroretinal cell death, despite ongoing hyperglycemia and weight loss. The eye is a special sensory organ, and these data show that cell loss in the nervous system, even in uncontrolled diabetes, can be prevented by IGF-I administration.
 ...
PMID:Systemic IGF-I treatment inhibits cell death in diabetic rat retina. 1663 41

This study addressed the mechanisms by which suckling regulates cell turnover and onset and maintenance of lactation of individual mammary glands of sows. The effects of no, transient (through 12 to 14 h postpartum), or regular suckling of individual glands during d 0 to 6 of lactation were studied in 5 sows. Nonsuckling was obtained by taping the glands to prevent access to the nipples. Visual scores confirmed that regularly suckled glands maintained lactation, whereas transiently suckled and nonsuckled glands regressed during lactation. Mammary gland biopsies were collected on d -5, 1, 2, 4, and 6 relative to farrowing in order to evaluate the cell turnover and to quantify the transcription of genes potentially involved in mammary cell turnover and function. The proportion of proliferating cells was greatest prepartum (13.1%). After farrowing, the proportion of proliferating cells declined in all glands, then remained low (5.6%) in nonsuckled glands and increased (P < 0.01) from an average of 7.5% on d 1 to 9.9% on d 6 in regularly suckled and transiently suckled glands. Transcriptional data were analyzed using a gamma-distributed, generalized linear mixed model. Abundance of alpha-lactalbumin mRNA (P < 0.01) increased in regularly suckled glands within the first day of lactation and remained elevated, whereas the expression in taped glands remained at the prepartum level. Prolactin receptor mRNA abundance decreased (P < 0.001), and IGFBP-5 mRNA abundance increased (P < 0.01) in nonsuckled and transiently suckled glands after parturition compared with regularly suckled glands. Mammary mRNA abundances of IGF-I, IGF-II, type I IGF receptor, and caspase 3 were minimally or inconclusively affected by the suckling regimens. In conclusion, suckling during the first 12 to 14 h postpartum is insufficient to initiate and maintain lactation until 24 to 36 h postpartum but sufficient to induce mammary cell proliferation for at least 6 d postpartum. Furthermore, a high prolactin receptor transcription and a low IGFBP-5 transcription seem important for maintaining a functional mammary gland during lactation.
 ...
PMID:Role of suckling in regulating cell turnover and onset and maintenance of lactation in individual mammary glands of sows. 1677 52

Anaplastic thyroid cancer (ATC) is an extremely aggressive tumor characterized by marked epithelial mesenchymal transition, which leads, almost invariably, to death. Peroxisomal proliferator-activated receptor (PPAR)-gamma agonists have recently emerged as potential antineoplastic drugs. To establish whether ATC could be a target of PPAR gamma agonists, we first examined PPAR gamma protein expression in a panel of six ATC cell lines and then studied the biologic effects of two PPAR gamma agonists, ciglitazone and rosiglitazone, that belong to the class of thiazolidonediones. PPAR gamma protein was present and functional in all ATC cell lines. Both ciglitazone and rosiglitazone showed complex biological effects in ATC cells, including inhibition of anchorage-dependent and -independent growth and migration, and increased apoptosis rate. Rosiglitazone-induced growth inhibition was associated with cell cycle arrest and changes in cell cycle regulators, such as an increase of cyclin-dependent kinases inhibitors p21(cip1) and p27(kip1), a decrease of cyclin D1, and inactivation of Rb protein. Rosiglitazone-induced apoptosis was associated with a decrease of Bcl-X(L) expression and caspase-3 and -7 activation. Moreover, rosiglitazone antagonized IGF-I biological effects by up-regulating phosphatase and tensin homolog deleted from chromosome 10 with subsequent inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway. Finally, rosiglitazone increased the expression of thyroid-specific differentiation markers. In conclusions, these data suggest that PPAR gamma agonists induce a partial reversion of the epithelial mesenchymal transition in ATC cells by multiple mechanisms. PPAR gamma agonists may, therefore, have a role in the multimodal therapy currently used to slow down ATC growth and dissemination.
 ...
PMID:Peroxisomal proliferator-activated receptor-gamma agonists induce partial reversion of epithelial-mesenchymal transition in anaplastic thyroid cancer cells. 1677 71

Ghrelin has recently emerged as pleiotropic regulator of a wide array of endocrine and non-endocrine functions. The former likely includes the control of gonadal function, as expression of ghrelin and its putative receptor, the GH secretagogue receptor type 1a (GHS-R1a), has been described in mammalian gonads, and direct effects of ghrelin in the control of testicular secretion and cell proliferation have been reported. Yet, the expression and/or functional role of ghrelin in gonads from non-mammalian species remain to be analyzed. The present study aimed to evaluate the expression of ghrelin and GHS-R genes in the chicken ovary, and to assess the potential involvement of ghrelin in the direct control of chick ovarian function. To this end, RT-PCR assays for ghrelin and GHS-R1a mRNAs were performed in ovarian tissue, and cultures of chicken ovarian cells were conducted in the presence of increasing doses (1, 10 or 100 ng/ml) of the ghrelin analog, ghrelin 1-18. Our results demonstrate that both ghrelin and GHS-R1a mRNAs are expressed in chick ovarian tissue. Moreover, challenge of ovarian granulosa cells with ghrelin 1-18 was able to induce markers of proliferation (i.e. expression of both PCNA and cyclin), and to modulate markers of apoptosis (i.e. decreased expression of caspase-3, bax, bcl-2 and TUNEL-positive cells). Moreover, ghrelin 1-18 increased the expression of PCNA, cyclin, bax and p53 in cultures of ovarian follicular fragments, where it also stimulated the release of progesterone, estradiol, arginine-vasotocin (AVT) and IGF-I, but not of testosterone. In conclusion, our study provides novel evidence for the gonadal expression of the genes encoding ghrelin and its cognate receptor in a non-mammalian species, i.e. the chicken ovary, and unravels the potential involvement of this newly discovered molecule in the control of key gonadal functions in the chick, such as proliferation, apoptosis, and hormone release.
 ...
PMID:Novel expression and functional role of ghrelin in chicken ovary. 1689 Oct 55

Leptin (L) is recognised as an important regulator of puberty and a factor which controls reproduction. Whole pig ovarian follicles were incubated with different doses of leptin (2, 20 and 200 ng/ml) added alone or in combination with 100 ng/ml of GH or 50 ng/ml of IGF-I. The expression of the functional long form leptin receptor (Ob-Rb) mRNA was examined by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) in follicular cells cultured with GH or IGF-I. Both GH and IGF-I increased leptin receptor expression in prepubertal pig ovaries. In separate experiments, the action of leptin on ovarian follicular steroidogenesis and cell apoptosis was examined. After 24 h of incubation with leptin alone or in combination with GH or IGF-I, oestradiol (E2) levels were determined in the culture medium while follicular tissue was used for the estimation of caspase-3 activity. Leptin increased E2 secretion and significantly diminished caspase-3 activity at all doses used. Both GH and IGF-I stimulated oestradiol secretion and decreased caspase-3 activity. No differences were demonstrable in oestradiol secretion and caspase-3 activity between cells treated with GH plus leptin and GH alone or cells treated with IGF-I plus leptin as compared to cultures treated with GH or IGF-I alone. However, GH diminished leptin-stimulated oestradiol secretion while IGF-I was without effect on it. Both GH and IGF-I reversed the anti-apoptotic action of leptin. In conclusion, we infer that (1) leptin directly affects ovarian function in prepubertal animals by its action on oestradiol secretion and cell apoptosis, (2) GH and IGF-I modulate the action of leptin, and (3) at least in part, the direct effect of GH/IGF-I on leptin production is due to an action on leptin receptor expression.
 ...
PMID:Gh and IGF-I increase leptin receptor expression in prepubertal pig ovaries: the role of leptin in steroid secretion and cell apoptosis. 1702 Jan 45

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.
 ...
PMID:Insulin-like growth factor-I is an important antiapoptotic factor for rat leydig cells during postnatal development. 1702 32

The importance of hormone therapy in affording protection against the sequelae of global ischemia in postmenopausal women remains controversial. Global ischemia arising during cardiac arrest or cardiac surgery causes highly selective, delayed death of hippocampal CA1 neurons. Exogenous estradiol ameliorates global ischemia-induced neuronal death and cognitive impairment in male and female rodents. However, the molecular mechanisms by which estrogens intervene in global ischemia-induced apoptotic cell death are unclear. Here we show that estradiol acts via the classical estrogen receptors, the IGF-I receptor, and the ERK/MAPK signaling cascade to protect CA1 neurons in ovariectomized female rats and gerbils. We demonstrate that global ischemia promotes early dephosphorylation and inactivation of ERK1 and the transcription factor cAMP-response element binding protein (CREB), subsequent down-regulation of the antiapoptotic protein Bcl-2, a known gene target of estradiol and CREB, and activation of caspase-3. Estradiol treatment increases basal phosphorylation of both ERK1 and ERK2 in hippocampal CA1 and prevents ischemia-induced dephosphorylation and inactivation of ERK1 and CREB, down-regulation of Bcl-2 and activation of the caspase death cascade. Whereas ERK/MAPK signaling is critical to CREB activation and neuronal survival, the impact of estradiol on Bcl-2 levels is ERK independent. These findings support a model whereby estradiol acts via the classical estrogen receptors and IGF-I receptors, which converge on activation of ERK/MAPK signaling and CREB to promote neuronal survival in the face of global ischemia.
 ...
PMID:MAPK signaling is critical to estradiol protection of CA1 neurons in global ischemia. 1713 46


<< Previous 1 2 3 4 5 6 7 Next >>