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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human prolactin (hPRL) has been shown to be one of the important survival/growth factors that promotes the proliferation of breast cancer cells in an autocrine/paracrine manner. In our recent studies, we demonstrated that a hPRL antagonist with a single amino acid substitution mutation (hPRL-G129R) was able to inhibit breast cancer cell proliferation via induction of apoptosis (1). In this study three independent yet related experiments were carried out regarding the effects of hPRL-G129R in breast cancer cells. We investigated the possible mechanism(s) of hPRL-G129R induced apoptosis in breast cancer cells. It is well documented that transforming growth factors (TGF) in conjunction with hormones such as estrogen and PRL play a major role in modulating the proliferation and apoptosis of mammary cells. We first investigated the relationships between hPRL/hPRL-G129R and TGFs. We show that hPRL is able to down-regulate TGF beta 1 (apoptotic factor) secretion and up-regulate TGF alpha (survival factor) secretion in a dose-dependent manner in T-47D cells. More importantly the hPRL antagonist up-regulates TGF beta 1 and down-regulates TGF alpha secretion. When hPRL-G129R was applied together with hPRL, it blocked the effects of hPRL. Secondly, we tested the possible involvement of caspases in hPRL-G129R induced apoptosis. We have shown that caspase-3 is activated by hPRL-G129R at a concentration of 250 ng/ml in T-47D breast cancer cells. Thirdly, we explored the additive effects of an anti-neoplastic drug, cisplatin, with the hPRL-G129R in T47D breast cancer cells. We show that cisplatin and hPRL-G129R when applied together resulted in about 40% growth inhibition in T-47D cells.
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PMID:In vitro studies of a prolactin antagonist, hPRL-G129R in human breast cancer cells. 1111 35

The expression of apoptosis-related proteins: TGF-beta1 (auto/paracrine inducer) and its receptor (TGF-betaRIII), Bax (promoter), Bcl-2 (inhibitor) and CPP-32 (executor of apoptosis) as well as the apoptotic cell number in mammary glands of 11 Polish White Improved goats in the course of the lactation cycle (peak of lactation: days 40-70, late lactation: days 208-256, drying off: days 267-340) was investigated. The immunohistochemical study demonstrated a significant increase in TGF-beta1 and TGF-betaRIII expression in the lobuloalveolar tissue from the early lactation to the dry period. Our recent study on HC11 mouse mammary epithelial cells [Cell. Mol. Biol. 46 (2000) 175] has revealed an inhibitory effect of prolactin on TGF-beta1 transcription, which may explain the low TGF-beta1 synthesis during lactogenesis and galactopoiesis and the increase in TGF-beta1 and TGF-betaIIIR expression in late lactation and dry period. Bax expression was the lowest in the peak of lactation, significantly increased in late lactation and remained elevated during drying off. Bcl-2 content was lower than Bax in all examined periods, but it increased significantly at the end of lactation, which suggests the survival of cells with the highest resistance to apoptogenic stimuli. The increase in Bcl-2 level in remnant lobuloalveolar tissue is probably the molecular mechanism that limits the rate of secretory tissue involution. The induction of CPP-32 (caspase 3) from the peak of lactation to dry period was accompanied by a progressive loss of mammary epithelial cells and the increase in apoptotic cell numbers but only in the dry period. The increase in the expression of examined proteins in the late lactation and the dry period indicates their involvement in the induction (TGF-beta1 and TGF-betaRIII), regulation (Bax and Bcl-2) and execution (CPP-32) of programmed cell death in the course of mammary gland involution. The lack of an increase in apoptotic cell number in late lactation, in spite of the evident decrease in total cell number, suggests milk as an alternative route (apart from phagocytosis) of apoptotic cells elimination from the mammary gland. The presented results provide new insights into the molecular mechanism of mammary cell apoptosis in goat and for this reason may have practical implications for control and regulation of mammary gland remodelling, which is a prerequisite for subsequent successful lactation.
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PMID:Expression of apoptosis-related proteins in mammary gland of goat. 1132 13

We previously showed in vivo and in vitro, that among the spermatogenic stages of the newt, prolactin (PRL) induces apoptosis specifically in the penultimate stage of secondary spermatogonia. In the current report, we demonstrate in vitro that cycloheximide (CHX), an inhibitor of protein synthesis, induces morphological apoptotic changes similar to those caused by PRL, such as chromatin condensation and apoptotic body formation. Next, we found that Z-VAD-fmk, an inhibitor of various caspases, suppressed the apoptosis induced by PRL and CHX, but ICE inhibitor Ac-YVAD-CHO or caspase-3 inhibitor Ac-DEVD-CHO did not. As high caspase activity was present in extracts of testes treated with CHX, we suggest that an unidentified caspase induces the morphological changes of apoptosis in newt spermatogonia.
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PMID:Caspase activity in newt spermatogonial apoptosis induced by prolactin and cycloheximide. 1138 56

The involvement of p53, Bax, cytochrome C and CPP-32 (caspase-3) in the molecular mechanism ofTGF-beta1-induced apoptosis in HC11 mouse mammary epithelial cells (MEC) was examined. Laser scanning cytometry (LSC) was applied for the quantitative analysis of expression and distribution of examined apoptosis-related proteins in the cytoplasmic (Cf) and nuclear (Nf) area. Maximal pixel of fluorescence (MP) parameter corresponding to aggregation of molecules in the cell was also measured. Confocal and immunoelectron microscopy were used as a complementary methods. Apoptosis induced by TGF-beta1 (2 ng/ml) was associated with the increase of Bax MP observed within 60 min. after cytokine administration, indicating aggregation of Bax in the cell. Immunoelectron microscopy revealed Bax aggregation on mitochondrial membranes, rough endoplasmic reticulum, Golgi apparatus, cytoskeleton, nuclear envelope and inside of nucleus. The accumulation of Bax in the nucleus was confirmed by compartmental Bax analysis, showing the increase of cell number with elevated Bax Nf in 2 hr after TGF-beta1 administration to the culture. The redistribution of Bax within the cell was dependent on its activation occurring by the cleavage at N-terminal epitope and exposure of BH3 domain. Bax aggregation on organelles was completely abolished by prolactin or IGF-I. TGF-beta1 increased p53 MP, evidently after 4 hr of cell culture exposure to this cytokine. p53 was accumulated first of all in the nucleus, which was shown by significant increase of p53 Nf/Cf ratio and increase of p53-related nuclear fluorescence on confocal images. TGF-beta1 decreased cytochrome C MP, which corresponded to its release from mitochondria and dissipation in the cytosol. It was accompanied by the increase of CPP-32 MP and concentration of 89 kDa product of PARP degradation in the nucleus. In conclusion, TGF-beta1 triggers apoptosis in MEC through mitochondrial pathway involving: activation and translocation of Bax to mitochondrial membranes, release of cytochrome C from mitochondria, activation of CPP-32 and degradation of its substrate - PARP in the nucleus. Activation and subcellular redistribution of Bax is inhibited by lactogenic hormones: prolactin and IGF-I.
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PMID:Molecular mechanism of TGF-beta1-induced apoptosis in HC11 mouse mammary epithelial cells (MEC). 1193 68

Successful pregnancy requires profound differentiation and reorganization of the uterine tissues including, as pregnancy progresses, extensive apoptosis of decidual tissue to accommodate the developing conceptus. We have previously shown a positive correlation between expression of activin A and apoptosis in the decidua and have also shown that expression of activin A occurs at the time when prolactin (PRL) receptors disappear from decidual cells. The goals of this study were to examine whether activin A plays a role in decidual apoptosis and whether expression of activin A in the decidua is regulated by PRL and placental lactogens. Studies were carried out using primary rat decidual cells, a decidual cell line (GG-AD), and PRL null mice. Treatment of decidual cells with activin A significantly increased DNA degradation, caspase 3 activity, and caspase 3 mRNA expression. However, this effect was observed only in the absence of endogenous activin production by these cells. Addition of follistatin to decidual cells that were producing activin A decreased both caspase 3 activity and mRNA expression. Similarly, addition of activin-blocking antibodies to cultures of GG-AD cells, which also produce activin A, caused a reduction in both DNA degradation and caspase 3 activity. PRL and placental lactogens caused an inhibition of activin A mRNA expression in primary decidual cells. Even more convincingly, decidua of PRL null mice expressed abundant activin A at a time when no expression of this hormone is detected in wild-type mice and treatment of PRL null mice with PRL caused a profound inhibition of activin A mRNA expression. In summary, our investigations into the role and regulation of decidual activin have revealed that activin A can induce cell death in the decidua and that its expression is under tight regulation by PRL and placental lactogens.
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PMID:Decidual activin: its role in the apoptotic process and its regulation by prolactin. 1260 60

The hypothesis that prolactin (PRL) functions as an immunomodulator was based on studies showing lymphocyte PRL receptors, and its effects on growth, differentiation, and apoptosis in lymphoid cells. However, studies of PRL (PRL-/-) and PRL receptor knockout mice indicated that PRL was not required for immune system development or function under basal conditions. Because PRL maintains survival in glucocorticoid (GC)-treated Nb2-T lymphocytes in vitro, and PRL and GCs are elevated during stress, we investigated whether PRL protected T cells in vivo from GC-induced apoptosis. Adrenalectomized mice [PRL -/-, undetectable PRL; pituitary grafted PRL-/- (PRL-/-Graft), elevated PRL; and PRL+/-, normal PRL] were treated with dexamethasone (DEX) or PBS. Thymocytes and splenocytes were isolated and annexin V labeling of phosphatidylserine, DNA fragmentation, and caspase-3 activation were assessed as indices of apoptosis. Total thymocytes and CD4+ and CD8+ T cells obtained from DEX-treated PRL-/- mice exhibited significantly increased annexin V binding. In contrast, binding was not altered by DEX in PRL-/-Graft thymocytes. In addition, DEX induced classic DNA fragmentation in PRL-/- thymocytes. Elevated serum PRL reduced this effect. Thymocytes from DEX-treated PRL-/- mice exhibited increased caspase-3 activation, which was inhibited in cells from PRL-/-Graft mice. Finally, elevated expression of X-linked inhibitor of apoptosis, XIAP, was observed in thymi from DEX-treated PRL -/-Graft mice. This is the first demonstration that elevated PRL antagonizes apoptosis in thymocytes exposed to GCs in vivo. These observations suggest that, under conditions of increased GCs, such as during stress, elevated PRL functions physiologically to maintain survival and function of T-lymphocytes.
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PMID:Prolactin suppresses glucocorticoid-induced thymocyte apoptosis in vivo. 1269 19

We have previously shown that the 16-kDa N-terminal fragment of human prolactin (16K hPRL) has antiangiogenic properties, including the ability to induce apoptosis in vascular endothelial cells. Here, we examined whether the nuclear factor-kappaB (NF-kappaB) signaling pathway was involved in mediating the apoptotic action of 16K hPRL in bovine adrenal cortex capillary endothelial cells. In a dose-dependent manner, treatment with 16K hPRL induced inhibitor kappaB-alpha degradation permitting translocation of NF-kappaB to the nucleus and reporter gene activation. Inhibition of NF-kappaB activation by overexpression of a nondegradable inhibitor kappaB-alpha mutant or treatment with NF-kappaB inhibitors blocked 16K hPRL-induced apoptosis. Treatment with 16K hPRL activated the initiator caspases-8 and -9 and the effector caspase-3, all of which were essential for stimulation of DNA fragmentation. This activation of the caspase cascade by 16K hPRL was also NF-kappaB dependent. These findings support the conclusion that NF-kappaB signaling plays a central role in 16K hPRL-induced apoptosis in vascular endothelial cells.
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PMID:The antiangiogenic factor 16K human prolactin induces caspase-dependent apoptosis by a mechanism that requires activation of nuclear factor-kappaB. 1279 71

Nitric oxide (NO) is an important modulator involved in immune regulation. Here, we describe conditions under which NO-donors induce apoptosis on Nb2 lymphoma cells, as evidenced by decreased cell viability and increased hypodiploid DNA content determined by flow cytometry. In addition, DNA fragmentation typical of apoptosis was shown by agarose gel electrophoresis. This apoptosis was accompanied by a significant increase of caspase-3-like enzymatic activity. Both ovine prolactin (oPRL) and ovine placental lactogen (oPL) exerted a protective effect on the NO-donor-induced apoptosis. Furthermore, dexamethasone (Dex)-induced cell death was also associated with caspase-3-like activity and oPL had the same potency as oPRL in its protective effect on Dex-induced apoptosis of Nb2 cells.
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PMID:Protective effect of prolactin and placental lactogen on NO-induced Nb2 lymphoma cell apoptosis. 1289 3

Nitric oxide (NO) plays a complex role in modulating programmed cell death. It can either protect the cell from apoptotic death or mediate apoptosis, depending on its concentration and the cell type and/or status. In this study, we demonstrate that long-term exposition to NO induces cell death of anterior pituitary cells from Wistar female rats. DETA NONOate (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate, 1 mm], a NO donor that releases NO for an extended period of time, decreased cellular viability and prolactin release from primary cultures of anterior pituitary cells. Morphological studies showed an increase in the number of cells with chromatin condensation and nuclear fragmentation at 24 and 48 h after DETA/NO exposure. DNA internucleosomal fragmentation was also observed at the same time. Reversibility of the NO effect on cellular viability and prolactin release was observed only when the cells were incubated with DETA/NO for less than 6 h. Most apoptotic cells were immunopositive for prolactin, suggesting a high susceptibility of lactotrophs to the effect of NO. The cytotoxic effect of NO is dependent of caspase-9 and caspase-3, but seems to be independent of oxidative stress or nitrosative stress. Our results show that the exposition of anterior pituitary cells to NO for long periods induces programmed cell death of anterior pituitary cells.
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PMID:Long-term treatment of anterior pituitary cells with nitric oxide induces programmed cell death. 1470 74

Both prolactin (PRL) and TGF-beta regulate cell survival in mammary epithelial cells, but their mechanisms of interactions are not known. In primary mammary epithelial cells and the HC11 mouse mammary epithelial cell line, PRL prevented TGF-beta-induced apoptosis, as measured by terminal deoxynucleotidyltransferase dUTP nick-end labeling staining and caspase-3 activation. This effect depended on phosphatidyl inositol triphosphate kinase (PI3K). PI3K activates a downstream serine/threonine kinase, Akt; therefore, we investigated the role of Akt in the interaction between PRL and TGF-beta signaling. Akt activity was inhibited by TGF-beta over a 20- to 60-min time course. In TGF-beta-treated cells, PRL disinhibited Akt in a PI3K-dependent manner. Expression of dominant negative Akt blocked the protective effect of PRL in TGF-beta-induced apoptosis. Transgenic mice overexpressing a dominant-negative TGF-beta type II receptor (DNIIR) in the mammary epithelium undergo hyperplastic alveolar development, and this effect was PRL dependent. Involution in response to teat sealing was slowed by overexpression of DNIIR; furthermore, Akt and forkhead phosphorylation increased in the sealed mammary glands of DNIIR mice. Thus, Akt appears to be an essential component of the interaction between PRL and TGF-beta signaling in mammary epithelial cells both in vitro and in vivo.
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PMID:Prolactin and transforming growth factor-beta signaling exert opposing effects on mammary gland morphogenesis, involution, and the Akt-forkhead pathway. 1496 11


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