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

The thiazolidinedione (TZD) family of PPARgamma agonists, especially troglitazone and ciglitazone, induce cell cycle arrest, differentiation, and apoptosis in cancer cells. Mounting evidence indicates that TZDs interfere with multiple signaling mechanisms independently of PPARgamma activation, which affect many aspects of cellular functions governing cell cycle progression and survival of cancer cells. Here, we review the "off-target" mechanisms that underlie the antitumor effects of TZDs with emphasis on three key pathways, namely, inhibition of Bcl-2/Bcl-xL function, proteasomal degradation of cell cycle- and apoptosis-regulatory proteins, and transcriptional repression of androgen receptor (AR) through Sp1 degradation. Relative to tumor cells, nonmalignant cells are resistant to these PPARgamma-independent antitumor effects, which underscores the translational potential of these agents. Furthermore, dissociation of these antitumor effects from their PPARgamma agonist activity provides a rationale for using TZDs as scaffolds for lead optimization to develop a novel class of antitumor agents with a unique mode of mechanism.
 ...
PMID:PPARgamma-independent antitumor effects of thiazolidinediones. 1879 May 59

The involvement of peroxisome proliferator-activated receptors (PPARs) in the cancer cell elimination through apoptosis is a generally accepted fact. However, some reports indicate that the activation of PPARgamma is directly responsible for carcinogenesis. Caco-2 cells, a human adenocarcinoma cells, were used as a model of colon cancer. Cell cultures (5 x 10(6) cell per dish) were pretreated for 24 h with PPAR gamma agonists ciglitazone (CI, 1 x 10(-6)M) and retinoic acid (RA, 1 x 10(-6)M) and part of the cultures were subsequently subjected to gamma-radiation (photons) with therapeutic dose of 2,5 Gy. Total cellular RNA and proteins (cytoplasmic and nuclear) were isolated 24h after cultures irradiation or 48 h after stimulation in the non irradiated part of experiment to preserve the equal growth time for all samples. gamma-Irradiation of the cells abolished nuclear translocation of PPARgamma under its agonists treatment and preserved PPARgamma in the cytoplasmic pool. But it did not affect the HSP 70 expression in response to ciglitazone and retinoic acid. Moreover, combined gamma-irradiation and CI/RA treatment of the cells changed the equilibrium between Bax and Bcl-2 mRNA to anti apoptotic state with increased expression of Bcl-2 and almost abolished expression of Bax. In conclusion, this paper provides an evidence for the anti-apoptotic action of PPARgamma agonists used along with the gamma-radiation. Moreover, it shows that the up-regulated HSP70, in response to PPARgamma agonists in gamma-irradiated cultures promotes cell survival.
 ...
PMID:Molecular mechanism of protection against chemically and gamma-radiation induced apoptosis in human colon cancer cells. 1881 38

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a multifunctional transcription factor that regulates adipogenesis, immunity and inflammation. Our laboratory previously demonstrated that PPARgamma ligands induce apoptosis in malignant B cells. While malignant B lineage cells such as B cell lymphoma express PPARgamma, its physiological function remains unknown. Herein, we demonstrate that silencing PPARgamma expression by RNAi in human Burkitt's type B lymphoma cells increased basal and mitogen-induced proliferation and survival, which was accompanied by enhanced NF-kappaB activity and increased expression of Bcl-2. These cells also had increased survival upon exposure to PPARgamma ligands and exhibited a less differentiated phenotype. In contrast, PPARgamma overexpression in B lymphoma cells inhibited cell growth and decreased their proliferative response to mitogenic stimuli. These cells were also more sensitive to PPARgamma-ligand induced growth arrest and displayed a more differentiated phenotype. Collectively, these findings support a regulatory role for PPARgamma in the proliferation, survival and differentiation of malignant B cells. These findings further suggest the potential of PPARgamma as a therapeutic target for B cell malignancy.
 ...
PMID:Peroxisome proliferator-activated receptor gamma overexpression and knockdown: impact on human B cell lymphoma proliferation and survival. 1901 32

The aims of this study were to assess the effects of a swimming session on the peripheral blood neutrophil and lymphocyte pro- and antioxidant system, identify any differences between the sexes and the regulatory mechanisms that might induce the immune cell adaptive response to exercise. Twenty-four swimmers (15 males, 9 females) participated in a one-hour swimming session at 75-80% of their maximal capacity. The session induced neutrophilia and decreased antioxidant enzyme activities and ascorbate levels in neutrophils. Malondialdehyde rose in neutrophils in males and females, whereas the carbonyl index only increased in males. Lymphocyte glutathione peroxidase activity was higher in males at baseline and rose as a consequence of exercise. The exercise decreased uncoupling protein-3 and Bcl-2 gene expression. The expression of PPARgamma coactivator-1 alpha (PGC-1alpha) correlated positively with that of sirtuin 3 (SIRT3) and catalase. In summary, a swimming session of one hour at 75-80% of maximal capacity produced oxidative damage in neutrophils and induced the antioxidant defences in lymphocytes. PGC-1alpha and SIRT3 appear to be key effectors of this adaptive response in lymphocytes. Both the neutrophil and lymphocyte response to exercise were slightly weaker in females than males.
 ...
PMID:Antioxidant regulatory mechanisms in neutrophils and lymphocytes after intense exercise. 1903 35

It has recently been shown that cannabinoids induce growth inhibition and apoptosis in different tumour cell lines. In the current study, the effects of WIN 55,212-2 (WIN), a synthetic and potent cannabinoid receptor agonist, are investigated in hepatoma HepG2 cells and a possible signal transduction pathway is proposed. In these cells, WIN induces a clear apoptotic effect which was accompanied by up-regulation of the death-signalling factors Bax, Bcl-X(S), t-Bid and down-regulation of the survival factors survivin, phospho-AKT, Hsp72 and Bcl-2. Moreover, WIN-induced apoptosis is associated with JNK/p38 MAPK pathway activation and mitochondrial depolarisation demonstrated by a cytofluorimetric assay. The results also show that in HepG2 cells WIN markedly increases the level of the transcription factor PPARgamma in a dose- and time-dependent manner. The addition of the PPARgamma antagonists GW9662 and T0070907 significantly reduces the effects of the drug on both cell viability and the levels of survivin, phospho-AKT and phospho-BAD, suggesting that PPARgamma plays a key role in WIN-induced apoptosis. Altogether, the results seem to indicate a potential therapeutic role of WIN in hepatic cancer treatment.
 ...
PMID:Apoptosis induced in HepG2 cells by the synthetic cannabinoid WIN: involvement of the transcription factor PPARgamma. 1905 57

Perfluorononanoate (PFNA), a perfluorinated alkyl acid containing nine carbon chains, has been detected in abiotic and biotic matrices worldwide. Although a few studies have reported toxic effects of PFNA, little information of the mechanism has been offered. In this study, the effects of PFNA exposure on thymus and the related mechanisms were investigated. Male rats were orally dosed with 0, 1, 3, or 5 mg PFNA/kg/day for 14 days. A significant decrease of body weight and thymus weight were observed in the rats receiving 3 or 5 mg PFNA/kg/day. Histopathological examination revealed dose-dependent increases in thymocyte apoptosis. Rats receiving 3 or 5 mg PFNA/kg/day exhibited increased interleukin (IL)-1 and decreased IL-2 concentrations in sera, whereas elevated IL-4 and cortisol levels only occurred in the highest dose group. Quantitative real-time PCR indicated that expression of peroxisome proliferator-activated receptor alpha (PPAR-alpha) was increased in the thymi of all dosed rats, and a similar trend occurred for PPAR-gamma in the two highest dose groups. The mRNA levels of c-Jun NH(2)-terminal kinase (JNK), nuclear factor-kappa B, p65 subunit, and inhibitory protein IkappaBalpha were unchanged; however, increased and decreased mRNA levels of p38 kinase were found in rats exposed to 3 or 5 mg PFNA/kg/day, respectively. Decreased Bcl-2 mRNA levels were observed in rats receiving 5 mg PFNA/kg/day. A significant increase in protein levels of phospho-JNK was found in all PFNA-treated rats. Phospho-p38 was significantly enhanced in 1 and 3 mg PFNA/kg/day groups, whereas phospho-IkappaBalpha remained consistent in all rats studied. Together, these data suggested that apart from the activation of PPARs, PFNA exposure in rats lead to the alteration of serum cytokines, which subsequently activated mitogen-activated protein kinase signaling pathways and potentially modulated the immune system. Additionally, increased serum cortisol and decreased expression of Bcl-2 in thymus likely contributed to the PFNA-induced thymocyte apoptosis.
 ...
PMID:Alterations of cytokines and MAPK signaling pathways are related to the immunotoxic effect of perfluorononanoic acid. 1919 29

Growth plate cartilage is responsible for long bone growth in children and adolescents and is regulated by vitamin D metabolites in a cell zone-specific manner. Resting zone chondrocytes (RC cells) are regulated by 24,25-dihydroxyvitamin D3 via a phospholipase D-dependent pathway, suggesting downstream phospholipid metabolites are involved. In this study, we showed that 24R,25(OH)2D3 stimulates rat costochondral RC chondrocytes to release lysophosphatidic acid (LPA) and, therefore sought to determine the role of LPA signaling in these cells. RC cells expressed the G-protein coupled receptors LPA1-5 and peroxisome proliferator-activated receptor gamma (PPAR-gamma). LPA and the LPA1/3 selective agonist OMPT increased proliferation and two maturation markers, alkaline phosphatase activity and [35S]-sulfate incorporation. LPA and 24R,25(OH)2D3's effects were inhibited by the LPA1/3 selective antagonist VPC32183(S). Furthermore, apoptosis induced by either inorganic phosphate or chelerythrine was attenuated by LPA, based on DNA fragmentation, TUNEL staining, caspase-3 activity, and Bcl-2:Bax protein ratio. LPA prevented apoptotic signaling by decreasing the abundance, nuclear localization, and transcriptional activity of the tumor-suppressor p53. LPA treatment also regulated the expression of the p53-target genes Bcl-2 and Bax to enhance cell survival. Collectively, these data suggest that LPA promotes differentiation and survival in RC chondrocytes, demonstrating a novel physiological function of LPA-signaling.
 ...
PMID:Lysophosphatidic acid signaling promotes proliferation, differentiation, and cell survival in rat growth plate chondrocytes. 1923 32

Among the carcinogenic chemicals of cigarette smoking, 4-(methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) is the most potent. The activation of peroxisome proliferator-activated receptor (PPAR)gamma can arrest the growth of lung cancer. We hypothesized that PPARgamma activation inhibits NNK-mediated proliferation of lung cancer cells. PPARgamma expression was increased in 94.7% human lung cancer tumor tissues, compared with their paired corresponding nontumor tissues. PPARgamma was also found to be abundant in all the lung cancer cell lines tested. Troglitazone dose-dependently inhibited the NNK-mediated proliferation of lung cancer cells that expressed PPARgamma. Troglitazone blocked NNK-induced up-regulation of HO-1, Bcl-2, and c-IAP2, and recovered Bad activity that was suppressed by NNK. NNK promoted the nuclear p21, whereas troglitazone increased cytosolic p21. Troglitazone increased PPARgamma transcriptional activity in NNK-treated cells and a PPARgamma dominant-negative inhibitor completely suppressed the action of troglitazone, indicating that troglitazone against NNK was PPARgamma-dependent. The findings reveal a novel molecular pathway of PPARgamma activation against cigarette smoking-related lung cancer.
 ...
PMID:PPARgamma activation extinguishes smoking carcinogen by inhibiting NNK-mediated proliferation. 1934 18

This study investigates the ability of a synthetic PPAR-gamma agonist, rosiglitazone (RGZ), to induce apoptosis in leukemia K562 cells. The results revealed that RGZ (>40 mmol/L) inhibits the growth of K562 cells and causes apoptosis in a time and dose-dependent manner. Apoptosis is observed clearly by Hoechst 33258 staining. Western blotting analysis demonstrates the cleavage of caspase-3 zymogen protein with the appearance of its 17-kD subunit and a dose-dependent cleavage of poly (ADP-ribose) polymerase. Furthermore, RGZ treatment down-regulates anti-apoptotic protein Bcl-2 and up-regulates pro-apoptotic protein Bax in a dosedependent manner after the cells are treated for 48 hours. Telomerase activity is decreased concurrently in a dosedependent manner. We therefore conclude that RGZ induces apoptosis in K562 cells in vitro, and that RGZ-induced apoptosis in K562 cells is highly correlated with activation of caspase-3, decreasing telomerase activity, down-regulation of the anti-apoptotic protein Bcl-2, and up-regulation of the pro-apoptotic protein Bax.
 ...
PMID:Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone--induced apoptosis in leukemia k562 cells and its mechanisms of action. 1948 36

Cardiovascular disease (CVD) is a leading cause of death and disabilities worldwide. Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists possess potent anti-inflammatory actions and have recently emerged as potential therapeutic agents for CVD. Here we show that H2O2 induced apoptosis in cardiomyocytes with a marked down-regulation of Bcl-2 protein. The PPARgamma agonist rosiglitazone protected cardiomyocytes from oxidative stress and apoptosis. Cardiomyocytes constitutively overexpressing PPARgamma were resistant to oxidative stress-induced apoptosis and protected against impairment of mitochondrial function. On the contrary, cells expressing a dominant negative mutant of PPARgamma were highly sensitive to oxidative stress. Cells overexpressing PPARgamma exhibited an almost 3 fold increase in Bcl-2 protein content; whereas, in PPARgamma dominant negative expressing cells, Bcl-2 was barely detected. Bcl-2 knockdown by siRNA in cells overexpressing PPARgamma results in increased sensitivity to oxidative stress, suggesting that Bcl-2 up-regulation mediated the protective effects of PPARgamma. These data suggest that, in oxidative stress-induced cardiomyocyte apoptosis, PPARgamma protects cells from oxidative stress through upregulating Bcl-2 expression. These findings provide further support for the use of PPARgamma agonists in ischemic cardiac disease.
 ...
PMID:PPAR gamma protects cardiomyocytes against oxidative stress and apoptosis via Bcl-2 upregulation. 1954 Sep 34


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