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)

Apoptosis and alterations in Bcl-2 and Bax messenger RNA (mRNA) and protein expression were examined in cultured human epidermal melanocytes following UVB irradiation (50 mJ/cm). The effects of various spectral ranges within UVB were investigated. A co-culture system was set up to study the interplay between melanocytes and keratinocytes in response to UVB. Melanocytes expressed high basal levels of the anti-apoptotic protein Bcl-2 compared with keratinocytes. Different wavelengths within the UVB spectrum induced diverse response patterns of Bcl-2 and Bax mRNA and had different apoptotic power. Both Bcl-2 and Bax mRNA were upregulated to preserve protein levels and only a slight increase in apoptosis was noted 24 h after UVB (lambda>305 nm). Increasing UVB between 280 and 305 nm enhanced apoptosis and upregulated Bcl-2, whilst Bax mRNA was unaltered. However, no change in protein levels was detected. A redistribution of Bax protein from different compartments within the cell may be more important than direct upregulation for the acceleration of apoptosis, but it cannot be excluded that other apoptotic pathways may be induced by shorter UVB wavelengths. The increase in apoptosis was significantly lower in melanocytes co-cultured with irradiated matched keratinocytes than in melanocytes from pure cultures, indicating that melanocytes are protected from UVB-induced apoptosis by the release of substance(s) from keratinocytes. This rescue response concurred with a fast and significant increase in Bcl-2 mRNA level in melanocytes.
Melanoma Res 2005 Feb
PMID:Wavelength-specific effects on UVB-induced apoptosis in melanocytes. A study of Bcl-2/Bax expression and keratinocyte rescue effects. 1571 15

Melanoma is the most aggressive form of skin cancer and advanced stages are invariably resistant to conventional therapeutic agents. Using bortezomib as a prototypic proteasome inhibitor, we have identified a novel and critical role of the proteasome in the maintenance of the malignant phenotype of melanoma cells that could have direct translational implications. Thus, melanoma cells from early, intermediate, and late stages of the disease could not sustain proteasome inhibition and underwent an effective activation of caspase-dependent and -independent death programs. This effect was tumor cell selective, because under similar conditions, normal melanocytes remained viable. Intriguingly, and despite of interfering with a cellular machinery in charge of controlling the half-life of the vast majority of cellular proteins, bortezomib did not promote a generalized disruption of melanoma-associated survival factors (including NF-kappaB, Bcl-2, Bcl-x(L), XIAP, TRAF-2, or FLIP). Instead, we identified a dramatic induction in vitro and in vivo of the BH3-only protein Noxa in melanoma cells (but not in normal melanocytes) in response to proteasome inhibition. RNA interference validated a critical role of Noxa for the cytotoxic effect of bortezomib. Notably, the proteasome-dependent regulation of Noxa was found to extend to other tumor types, and it could not be recapitulated by standard chemotherapeutic drugs. In summary, our results revealed Noxa as a new biomarker to gauge the efficacy of bortezomib specifically in tumor cells, and provide a new strategy to overcome tumor chemoresistance.
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PMID:Differential regulation of noxa in normal melanocytes and melanoma cells by proteasome inhibition: therapeutic implications. 1602 31

The aim of this study was to clarify the roles of the tumour proliferation marker Ki-67, the anti-apoptotic protein Bcl-2 and the cell cycle regulator p53 in primary cutaneous and metastatic melanoma. One hundred and seventeen primary melanomas and 18 metastatic tissue samples were analysed for immunohistochemical expression of Ki-67, Bcl-2 and p53. The staining results were correlated with disease progression and clinical outcome. The patient population comprised patients diagnosed with melanoma between 1988 and 1991. The clinical follow-up period for disease recurrence was 4.6 years (median; range, 0.2-7.5 years) and the follow-up period for overall survival was 10.0 years (median; range, 8.6-15.6 years). Ki-67 expression was not a prognostic factor in primary melanoma. High Bcl-2 expression was associated with such adverse prognostic factors as male gender, old age of the patient and tumour ulceration. High Bcl-2 expression was also associated with an adverse prognosis in intermediate-thickness (1.01-4.0 mm) melanomas (n=52) for disease-free (P=0.09) and overall (P=0.08) survival. In multivariate analysis, tumour thickness was the strongest prognostic factor for disease-free survival (P<0.01). High p53 expression indicated a poorer prognosis (P=0.05). In metastatic melanoma, the expression levels of Bcl-2 and p53 were lower than those in their primary counterparts (P=0.08 for each). Ki-67 expression showed no remarkable changes. It can be concluded that high p53 expression in tumour cells is associated with a poorer prognosis in primary melanoma, and high Bcl-2 expression in tumour cells is an adverse prognostic marker in intermediate-thickness primary melanoma.
Melanoma Res 2005 Oct
PMID:Ki-67, Bcl-2 and p53 expression in primary and metastatic melanoma. 1617 64

The Fas/FasL signalling system plays an important role in chemotherapy-induced apoptosis in several different cell types. After interferon-gamma (IFN-gamma) treatment, we have previously reported a significant increase in Fas expression in oral malignant melanoma cell lines (MMN9, PMP, MAA, HMG) in vitro, and combination therapy using IFN-gamma and anti-Fas antibody (CH-11) has shown a synergistic anti-proliferative effect in MMN9 cells. There have been several in-vitro studies using CH-11, but there are few reports of its anti-tumour effect in vivo. In this study, we investigated experimental therapy using anti-Fas antibody against MMN9 in vivo in a mouse model, and histologically examined tumour tissue removed from BALB/c nude mice. Animals that received both IFN-gamma and CH-11 showed a 53.8% increase in anti-tumour effect (P=0.0018) 20 days after the first administration. In the histological study, the combined administration group tested positive in terminal deoxynucleotidyl transferase-mediated nick end labelling staining, and showed significantly increased levels of Fas expression on immunostaining compared with the vehicle group. These results show the efficacy of anticancer therapy using IFN-gamma and anti-Fas antibody via the modulation of Fas-mediated apoptosis. Moreover, inhibition of IFN-gamma/CH-11-induced apoptosis with a general caspase inhibitor (benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone) reduced cell death significantly in vitro. Bcl-2 cleavage did not occur under these conditions, suggesting a relationship between caspase activation and Bc1-2 cleavage in MMN9 cells.
Melanoma Res 2005 Oct
PMID:Experimental therapy using interferon-gamma and anti-Fas antibody against oral malignant melanoma cells. 1617 66

Melanoma cells depend on sustained proteasomal function for survival. However, bortezomib, the first proteasome inhibitor in clinical use, is not sufficient to improve the poor prognosis of metastatic melanoma patients. Since the proteasome is also expressed in all normal cell compartments, it is unclear how to enhance the efficacy of bortezomib without exacerbating secondary toxicities. Here, we present pharmacological and genetic analyses of mechanisms of resistance to proteasome inhibition. We focused on Bcl-2, Bcl-x(L) and Mcl-1 as main antiapoptotic factors associated with melanoma progression. Despite an efficient blockage of the proteasome, bortezomib could not counteract the intrinsically high levels of Bcl-2 and Bcl-x(L) in melanoma cells. Moreover, Mcl-1 was only downregulated at late time points after treatment. Based on these results, a combination treatment including (-)-gossypol, an inhibitor of Mcl-1/Bcl-2/Bcl-x(L), was designed and proven effective in vivo. Using a specific RNA interference approach, the survival of bortezomib-treated melanoma cells was found to rely primarily on Mcl-1, and to a lesser extent on Bcl-x(L) (but not on Bcl-2). Importantly, neither Mcl-1 nor Bcl-x(L) inactivation affected the viability of normal melanocytes. This hierarchical requirement of Bcl-2 family members for the maintenance of normal and malignant cells offers a therapeutic window to overcome melanoma chemoresistance in a tumor cell-selective manner.
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PMID:Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins. 1754 28

Microphthalmia-associated transcription factor (Mitf) is essential for melanocyte development and function and regulates anti-apoptotic Bcl2 expression. We hypothesized that cellular deficiency of Mitf can influence melanocyte survival in response to ultraviolet (UV) radiation. Primary melanocyte cultures were prepared from neonatal wild-type mice and congenic animals heterozygous for Mitf mutations Mitf (mi-vga9/+) and Mitf(Mi-wh/+) and exposed to UV irradiation. Wild-type melanocytes were more resistant to UV-induced apoptosis than melanocytes partially deficient in Mitf activity, as determined by relative levels of intracellular melanin and relative activation of Mitf target genes Tyr, Tyrp1, Dct, and Cdk2. Comparative experiments with wild-type cells and congenic albino melanocytes demonstrated that these differences are not due to differences in melanin content, implicating Mitf as a primary determinant of UV-dependent melanocyte survival. Mitf activity correlated directly with resistance to UV-induced apoptosis in melanocytes. Mitf was important not only for regulating the expression of anti-apoptotic Bcl-2 following UV irradiation, but also the expression of the pro-apoptotic BH3-only Bad protein and activation of the extrinsic apoptotic pathway. Hence, Mitf is a multifaceted regulator of UV-induced apoptosis in melanocytes.
Pigment Cell Melanoma Res 2009 Jun
PMID:Mitf dosage as a primary determinant of melanocyte survival after ultraviolet irradiation. 1919 12

Melanoma is a particularly aggressive tumor type that exhibits a high level of resistance to apoptosis. The serine/threonine kinase B-RAF is mutated in 50% to 70% of melanomas and protects melanoma cells from anoikis, a form of apoptosis induced by lack of adhesion or adhesion to an inappropriate matrix. Mutant B-RAF down-regulates two BH3-only proapoptotic proteins, Bim(EL) and Bad. BH3-only proteins act, at least in part, by sequestering prosurvival Bcl-2 family proteins and preventing them from inhibiting the mitochondrial apoptotic pathway. Several Bcl-2 proteins are up-regulated in melanoma; however, the mechanisms of up-regulation and their role in melanoma resistance to anoikis remain unclear. Using RNA interference, we show that depletion of Mcl-1 renders mutant B-RAF melanoma cells sensitive to anoikis. By contrast, minor effects were observed following depletion of either Bcl-2 or Bcl-(XL). Mcl-1 expression is enhanced in melanoma cell lines compared with melanocytes and up-regulated by the B-RAF-MEK-extracellular signal-regulated kinase 1/2 pathway through control of Mcl-1 protein turnover. Similar to B-RAF knockdown cells, adhesion to fibronectin protected Mcl-1 knockdown cells from apoptosis. Finally, expression of Bad, which does not sequester Mcl-1, further augmented apoptosis in nonadherent Mcl-1 knockdown cells. Together, these data support the notion that BH3 mimetic compounds that target Mcl-1 may be effective for the treatment of melanoma in combinatorial strategies with agents that disrupt fibronectin-integrin signaling.
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PMID:Mcl-1 is required for melanoma cell resistance to anoikis. 1937 83

The objective of this study is as follows. Inhibitor of growth (ING) 4 is a novel member of the ING family. It has been thought to play an inhibitory role in several malignancies through its involvment in gene transcription, apoptosis, cell cycle control, and tumor angiogenesis. The involvement of ING4 in melanomagenesis remains unknown. The purpose of this study was to investigate the inhibitory effects of ING4 on melanoma and its mechanisms. The method used was to construct recombinant plasmid pcDNA3.1-ING4 and transfect it into the human melanoma cell line M14. The effects and mechanisms of ING4 on proliferation and apoptosis of M14 cells were analyzed in vitro according to MTT assay, colony formation assay, and TUNEL assay. The detection of the expression of cell cycle or apoptosis regulators in transfected M14 cells was carried out by western blot analysis. Moreover, the level of ING4 in melanoma tissues was examined by immunohistochemistry. The expression of ING4 was markedly reduced in cutaneous melanoma tissues. Overexpression of ING4 could induce growth suppression and apoptosis enhancement in M14 cells, and also induce the upregulation of p27, Bax and Cyt-c, and the downregulation of cyclinD1, SKP2, Bcl-2, and caspase-3. In conclusion, ING4, as a novel tumor suppressor, has a potential role in growth suppression and apoptosis enhancement of melanoma M14 through the activation of the mitochondrial-induced apoptotic pathway and the hindrance of cell cycle progression. The deregulation of ING4 might be involved in melanomagenesis.
Melanoma Res 2009 Feb
PMID:Inhibitor of growth 4 is involved in melanomagenesis and induces growth suppression and apoptosis in melanoma cell line M14. 1943 Apr 1

Melanoma incidence has increased over the last few decades and metastatic melanoma is one of the hardest malignancies to treat. Thus, novel approaches are needed for an effective management of melanoma. Interferon-alpha2b (IFN), an immunomodulatory cytokine commonly used in melanoma treatment, has shown marginal efficacy and often results in discontinuation of therapy due to toxicity. We earlier demonstrated that epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea, caused cell cycle arrest and apoptosis of human melanoma cells via modulation in cki-cyclin-cdk machinery and Bcl-2 family proteins. This study was undertaken to determine if EGCG could enhance the anti-proliferative effects of IFN. In this study, we demonstrated that EGCG and/or IFN treatments to melanoma cells resulted in a marked (1) decrease in cell proliferation and colony formation ability, and (2) induction of apoptosis. Interestingly, the combination was found to be more effective than either of the agents alone. Further, the anti-proliferative effects of EGCG and/or IFN were accompanied with an increase in Fas protein levels and a decrease in nuclear factor NFkappaB/p65 in the nucleus as well as NFkappaB promoter activity. EGCG and/or IFN also resulted in an increase in Fas-L mediated apoptosis. Further, EGCG and/or IFN treatments resulted in a decrease in melanoma tumor growth and protein levels of proliferation marker PCNA, in athymic nude mice implanted with melanoma tumors. The combination of the two modalities demonstrated a better response than either of them alone. Our data suggest that EGCG could impart therapeutic advantage if used in conjunction with IFN.
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PMID:(-)-Epigallocatechin-3-gallate (EGCG) sensitizes melanoma cells to interferon induced growth inhibition in a mouse model of human melanoma. 1955 Jan 55

Melanoma is a tumor with a very low cure rate once metastasized. Although many genes important for melanoma induction, transformation, and metastasis have been identified, the process of melanomagenesis is only partly understood. Melanoma mediators are easiest to investigate in cell culture models, but animal models are required to evaluate their importance in the context of the whole organism. Here, we describe a transgenic melanoma model in medaka. The oncogenic receptor tyrosine kinase, Xmrk, responsible for melanoma formation in Xiphophorus, was stably expressed under the control of a pigment cell-specific promoter. The transgenic fish developed pigment cell tumors with a penetrance of 100%. The model was used for monitoring the in vivo relevance of several apoptosis and differentiation genes, and for induction of melanoma-relevant signal transduction pathways. We found that Stat5 activation, and Mitf and Bcl-2 levels correlated with a more aggressive stage of the malignancy. Interestingly, different types of pigment cell tumors occurred depending on the genetic background, namely invasive melanoma, uveal melanoma, or exophytic and less aggressive pigment cell tumors called xanthoerythrophoroma. Furthermore, on p53 mutant background, the expression of xmrk led to the appearance of giant focal pigment cell tumors, whereas tumor onset was unchanged compared with wild-type medaka.
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PMID:A mutated EGFR is sufficient to induce malignant melanoma with genetic background-dependent histopathologies. 2001 Aug 63


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