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)

A recent clinical trial (Chwalisz K, Larsen L, Mattia-Goldberg C, Edmonds A, Elger W, Winkel CA. Fertil Steril 87: 1399-1412, 2007) has demonstrated that the selective progesterone receptor modulator asoprisnil efficiently causes the shrinkage of uterine leiomyoma. The present study was conducted to examine whether asoprisnil elicits endoplasmic reticulum (ER) stress-induced apoptosis in cultured human uterine leiomyoma cells. After subculture in phenol red-free DMEM supplemented with 10% FBS for 120 h, cultured cells were stepped down to serum-free conditions with or without graded concentrations of asoprisnil. ER stress-associated and apoptosis-related proteins were assessed by reverse transcription-PCR analysis or Western blot analysis. RNA interference of growth-arrest- and DNA-damage-inducible gene 153 (GADD153) was performed using small interfering RNA. Terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL)-positive rates were assessed by TUNEL assay. Compared with untreated control cultures, treatment with 10(-7) M asoprisnil significantly (P < 0.05) increased the protein contents of ubiquitin at 2 h and phospho-double-stranded RNA-activated protein kinase-like ER kinase, phospho-eukaryotic initiation factor 2alpha, activating transcription factor 4, and glucose-regulated protein 78 kDa at 4 h, followed by the significant (P < 0.05) increase in GADD153 protein content at 6 h and cleaved poly(adenosine 5'-diphosphate ribose)polymerase (PARP) at 8 h. RNA interference of GADD153 suppressed protein contents of asoprisnil-induced cleaved PARP, Bax, Bak, GADD34, and tribbles-related protein 3 (TRB3) and TUNEL-positive rate but attenuated asoprisnil-induced reduction in Bcl-2 protein content in cultured leiomyoma cells. These results suggest that asoprisnil elicits ER stress-induced apoptosis in cultured leiomyoma cells and that GADD153 plays a role in asoprisnil-induced apoptosis by modulating the Bcl-2 family of proteins, GADD34, and TRB3.
 ...
PMID:Selective progesterone receptor modulator asoprisnil induces endoplasmic reticulum stress in cultured human uterine leiomyoma cells. 1765 52

Dysfunction of the ubiquitin-proteasome system (UPS) and accumulation of iron in substantia nigra (SN) are implicated in the pathogenesis of Parkinson's disease (PD). UPS dysfunction and iron misregulation may reinforce each other's contribution to the degeneration of dopamine (DA) neurons. In the present study, we use a new brain-permeable iron chelator, VK-28 [5-(4-(2-hydroxyethyl) piperazin-1-yl (methyl)-8-hydroxyquinoline], and its derivative M30 [5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline] in vivo to test their neuroprotective and neurorestorative properties against proteasome inhibitor (lactacystin) -induced nigrostriatal degeneration. Bilateral microinjections of lactacystin (1.25 microg/side) into the mouse medial forebrain bundle were performed. Administration of VK-28 (5 mg/kg, once a day) or M30 (5 mg/kg, once a day) was applied intraperitoneally 7 days before or after the lactacystin microinjection until the mice were sacrificed 28 days after microinjection. We found that VK-28 and M30 both significantly improved behavioral performances and attenuated lactacystin-induced DA neuron loss, proteasomal inhibition, iron accumulation, and microglial activation in SN. In addition, M30 restored the Bcl-2 level, which was suppressed after lactacystin injection. These findings suggest that brain-permeable iron chelators can improve DA neuron survival under UPS impairment. Furthermore, M30, a derivative of VK-28 and neuroprotective agent rasagiline, may serve as a better neuroprotective therapy for PD.
 ...
PMID:Prevention and restoration of lactacystin-induced nigrostriatal dopamine neuron degeneration by novel brain-permeable iron chelators. 1769 Jan 54

The ubiquitin-proteasome system is the major non-lysosymal system for degrading proteins in the cell; the work leading to its discovery was awarded the Nobel Prize in Chemistry in 2004. In addition to small ubiquitin-like modifiers (e.g. Sumo and Nedd8), ubiquitin is involved in the complex regulation of the levels and function of many proteins and signaling pathways involved in determining cell fate. The cell death regulatory proteins, such as Bcl-2 family proteins and caspases are targeted for degradation by the ubiquitin proteasome system (UPS). In addition to mediating the degradation of proteins, the UPS regulates function and translocation of proteins, many of which play a role in the determination of cell fate. For example the UPS can regulate the activity of transcription factors, such as P53, NF-kappaB and HIF-1 alpha, which control the expression of protein mediators of cell death. Aberrant UPS function has been reported in multiple neuropathologies including Parkinson's diseases and ischemia. With the number of ubiquitin conjugating and de-conjugating enzymes reaching close to the levels of protein kinases and phosphatases, it is clear that ubiquitination is an important biological regulatory step for proteins.
 ...
PMID:Ubiquitin-proteasome system as a modulator of cell fate. 1798 2

In Parkinson's and other neurodegenerative diseases, a therapeutic strategy has been proposed to halt progressive cell death. Propargylamine derivatives, rasagiline and (-)deprenyl (selegiline), have been confirmed to protect neurons against cell death induced by various insults in cellular and animal models of neurodegenerative disorders. In this paper, the mechanism and the markers of the neuroprotection are reviewed. Propargylamines prevent the mitochondrial permeabilization, membrane potential decline, cytochrome c release, caspase activation and nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase. At the same time, rasagiline induces anti-apoptotic pro-survival proteins, Bcl-2 and glial cell-line derived neurotrophic factor, which is mediated by activated ERK-NF-kappaB signal pathway. DNA array studies indicate that rasagiline increases the expression of the genes coding mitochondrial energy synthesis, inhibitors of apoptosis, transcription factors, kinases and ubiquitin-proteasome system, sequentially in a time-dependent way. Products of cell survival-related gene induced by propargylamines may be applied as markers of neuroprotection in clinical samples.
 ...
PMID:Neuroprotection by propargylamines in Parkinson's disease: intracellular mechanism underlying the anti-apoptotic function and search for clinical markers. 1798 85

The most significant complication of testicular torsion is loss of the testis, which may lead to impaired fertility. Molecular mechanisms how spermatogenesis impairs owing to testicular torsion remain unknown. This investigation, by using mouse model of testicular torsion, was undertaken to gain insight into the cellular and molecular mechanism underlying torsion-induced germ cell loss. Male mice were subjected to 2h ischemia-inducing torsion, and testes were examined at 24, 48, and 72h after the repair of torsion (reperfusion). Ischemia-reperfusion (IR) of the testes resulted in germ cell, mostly in spermatogonia, apoptosis, which was revealed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) technique. At 24h after torsion repair germ cell apoptosis reached peak, then decreased until 72h repair. Western blots showed that apoptotic proteins (p53, Caspase-3 and -9) gradually were upregulated at 48h reperfusion, however, anti-apoptotic proteins (Bcl-2 and BDNF) were downregulated in the relevant IR treatment. IR injury induced CHOP protein appearance with maximum expression at 24h of reperfusion. Furthermore, the germ cell apoptosis triggered downregulation of ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) at both mRNA and protein levels. To test further whether ubiquitination was involved in IR stress, both mono- and poly-ubiquitin levels in IR stress condition were examined, which showed that both mono- and poly-ubiquitin expression significantly impaired. These results provide evidences of UCH-L1/ubiquitination signaling to the testis IR injury in vivo.
 ...
PMID:Role of UCH-L1/ubiquitin in acute testicular ischemia-reperfusion injury. 1807 May 98

Bcl-2 family member Bid is subject to autoinhibition; in the absence of stimuli, its N-terminal region sequesters the proapoptotic Bcl-2 homology 3 (BH3) domain. Upon proteolytic cleavage in its unstructured loop, Bid is activated, although structural data reveal no apparent resulting conformational change. We found that, upon Bid cleavage, the N-terminal fragment (tBid-N) is ubiquitinated and degraded, thus freeing the BH3 domain in the C-terminal fragment (tBid-C). Ubiquitination of tBid-N is unconventional because acceptor sites are neither lysines nor the N terminus. Chemical approaches implicated thioester and hydroxyester linkage of ubiquitin and mutagenesis implicated serine and possibly threonine as acceptor residues in addition to cysteine. Acceptor sites reside predominantly but not exclusively in helix 1, which is required for ubiquitination and degradation of tBid-N. Rescue of tBid-N from degradation blocked Bid's ability to induce mitochondrial outer membrane permeability but not mitochondrial translocation of the cleaved complex. We conclude that unconventional ubiquitination and proteasome-dependent degradation of tBid-N is required to unleash the proapoptotic activity of tBid-C.
 ...
PMID:Apoptosis induction by Bid requires unconventional ubiquitination and degradation of its N-terminal fragment. 1816 54

Uveal melanoma is the most common primary intra-ocular malignancy in adults. Overall mortality rate remains high because of the development of metastatic disease, which is highly resistant to systemic therapy. Improved understanding of the molecular pathogenesis of cancers has led to a new generation of therapeutic agents that interfere with a specific pathway critical in tumor development or progression. Although no specific genes have been linked to the pathogenesis of uveal melanoma, which differs from that of cutaneous melanoma, progress has been made in identifying potential targets involved in uveal melanoma apoptosis, proliferation, invasion, metastasis, and angiogenesis. This review focuses on the prospects for improving the systemic therapy of uveal melanoma using molecularly targeted agents that are currently in clinical use as well as agents being tested in clinical trials. Preclinical studies suggest potential benefit of inhibitors of Bcl-2, ubiquitin-proteasome, histone deactylase, mitogen-activated protein kinase and phosphatidylinositol-3-kinase-AKT pathways, and receptor tyrosine kinases. Modifiers of adhesion molecules, matrix metalloproteinase, and angiogenic factors also have demonstrated potential benefit. Clinical trials of some of these approaches have been initiated in patients with metastatic uveal melanoma as well as in the adjuvant setting after primary therapy.
 ...
PMID:Targeted therapy for uveal melanoma. 1822 59

BNIP3 is a unique pro-apoptotic protein which belongs to the BH3-only subset of the Bcl-2 family and localizes on mitochondrial membrane. Despite the inherent difficulty of identifying binding partners for membrane proteins, several binding partners for BNIP3 have been identified. In this study, a modified split-ubiquitin membrane yeast two-hybrid system was constructed and used to identify acetyl-Coenzyme A acyltransferase 2 (ACAA2) as a new BNIP3 binding partner. The interaction between BNIP3 and ACAA2 was confirmed by pull-down and co-immunoprecipitation assays. ACAA2 was also found to co-localize with BNIP3 in mitochondria. Furthermore, the apoptosis induced by over-expressed BNIP3 via transfection or hypoxia treatment was abolished by ACAA2 in human hepatocellular carcinoma HepG2 cells and osteosarcoma U-2 OS cells. These results strongly suggest that ACAA2 be a functional BNIP3 binding partner and provide a possible linkage between fatty acid metabolism and apoptosis of cells.
 ...
PMID:Acetyl-Coenzyme A acyltransferase 2 attenuates the apoptotic effects of BNIP3 in two human cell lines. 1837 12

Cobalt promotes apoptosis in multiple cell systems, however, the molecular mechanisms that influence cobalt-induced apoptosis are not fully understood. We investigated mechanisms of cobalt chloride induced apoptosis in HCT116 colorectal cancer cells. Cobalt chloride induced dose dependent apoptosis in HCT116 cells (250-750 muM) which, at higher concentrations (500-750 muM), was associated with an increase in the expression of the Bcl-2-related Mcl-1 survival protein. Cobalt chloride caused the accumulation of higher molecular weight ubiquitin-conjugates of Mcl-1 in intact HCT116 cells and inhibited the activity of the trypsin-like site of the 20S proteasome in an in vitro assay. Although siRNA-mediated knockdown of Mcl-1 increased apoptosis in HCT116 cells, the combination of Mcl-1 siRNA and cobalt chloride induced very high levels of cell killing. Therefore, inhibition of the proteasome by cobalt chloride leads to the accumulation of Mcl-1 which acts to limit cobalt chloride induced apoptosis.
 ...
PMID:Inhibition of proteasomal degradation of Mcl-1 by cobalt chloride suppresses cobalt chloride-induced apoptosis in HCT116 colorectal cancer cells. 1854 7

Hexavalent chromium [Cr(VI)] compounds are redox cycling environmental carcinogens that induce apoptosis as the primary mode of cell death. Defects in apoptosis regulatory mechanisms contribute to carcinogenesis induced by Cr(VI). Activation of apoptosis signaling pathways is tightly linked with the generation of reactive oxygen species (ROS). Likewise, ROS have been implicated in the regulation of Cr(VI)-induced apoptosis and carcinogenicity; however, its role in Cr(VI)-induced apoptosis and the underlying mechanism are largely unknown. We report that ROS, specifically superoxide anion (.O(-)(2), mediates Cr(VI)-induced apoptosis of human lung epithelial H460 cells. H460 rho(0) cells that lack mitochondrial DNA demonstrated a significant decrease in ROS production and apoptotic response to Cr(VI), indicating the involvement of mitochondrial ROS in Cr(VI)-induced apoptosis. In agreement with this observation, we found that Cr(VI) induces apoptosis mainly through the mitochondrial death pathway via caspase-9 activation, which is negatively regulated by the antiapoptotic protein Bcl-2. Furthermore, .O(-)(2) induced apoptosis in response to Cr(VI) exposure by downregulating and degrading Bcl-2 protein through the ubiquitin-proteasomal pathway. This study reveals a novel mechanism linking .O(-)(2) with Bcl-2 stability and provides a new dimension to ROS-mediated Bcl-2 downregulation and apoptosis induction.
 ...
PMID:Superoxide-mediated proteasomal degradation of Bcl-2 determines cell susceptibility to Cr(VI)-induced apoptosis. 1854 62


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>