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)

We have previously observed that near-infrared (IR) pre-irradiation protects normal human dermal fibroblasts from ultraviolet (UV) cytotoxicity in vitro. Here, we show that IR pre-irradiation of human fibroblasts inhibited UVB activation of caspase-9 and -3, leading us to study early events in the mitochondrial apoptotic pathway after IR irradiation. IR irradiation led to a partial release of cytochrome c and Smac/Diablo but not apoptosis-inducing factor (AIF). This was accompanied by a slight but transient decrease in the mitochondrial membrane potential (Deltapsim) and by the insertion of Bax into mitochondrial membrane. Early apoptotic events in the mitochondrial pathway thus occurred after IR irradiation despite a lack of caspase-9 and -3 activation. This could be explained by the induction by IR of the expression of heat shock protein Hsp27, which is known to prevent apoptosome assembly. Furthermore, the balance between pro-apoptotic (i.e., Bax) and anti-apoptotic (i.e., Bcl-2 or Bcl-xL) proteins, which was rather pro-apoptotic after IR exposure, became anti-apoptotic 24 h later, suggesting a protective effect. Together, these actions could also contribute to prepare the cell to resist UVB-triggered apoptosis. Finally, isolated rat liver mitochondria-released cytochrome c in response to IR, demonstrating that mitochondria were a primary target of IR radiation.
J Invest Dermatol 2004 Nov
PMID:Infrared radiation affects the mitochondrial pathway of apoptosis in human fibroblasts. 1548 67

While enhanced expression of cyclooxygenase (COX)-2 has been observed in human skin epidermal cancer, the mechanisms underlying COX-2 expression have not been completely elucidated. Recently, a role for the phosphatidylinositol-3 (PI3) kinase pathway in COX-2 expression has attracted attention. We investigated COX-2 expression, PI3 kinase activity, and the phosphorylation level of Akt, a downstream effector of PI3 kinase, in the human skin cancer cell line HSC-5. Compared to the nontumorigenic keratinocyte HaCaT, in HSC-5 cells, COX-2 protein expression and PI3 kinase activity were increased. The PI3 kinase inhibitor LY294002 reduced COX-2 expression in HSC-5 cells and, contrary to our expectation, the phosphorylation of Akt was significantly decreased. The expression of Bcl-2, which is regulated by Akt, was reduced, and apoptosis was induced in HSC-5 cells compared to HaCaT cells. COX-2 inhibitor NS398 up-regulated Akt phosphorylation. These results imply that constitutively over-expressed COX-2 down-regulates the Akt phosphorylation through a negative feedback mechanism.
J Dermatol 2004 Jul
PMID:Negative feedback regulation of phosphatidylinositol 3-kinase/Akt pathway by over-expressed cyclooxygenase-2 in human epidermal cancer cells. 1549 14

Stem cell factor (SCF) and its receptor, KIT, are essential to the migration and differentiation of melanocytes during embryogenesis. We previously demonstrated that apoptosis is induced by blocking survival function of the SCF/KIT interaction in a mouse neural crest cell (NCC) primary culture. Using the NCCmelb4 cell line, we investigated the occurrence of apoptosis in the cultured cells when KIT receptors were blocked by the monoclonal anti-KIT antibody (ACK2). Apoptosis following treatment with ACK2 was detected by DNA fragmentation assay, in situ apoptosis detection, and electron microscopy. We noted a decrease in extracellular signal-related kinase (ERK) and ribosomal S6 kinase (RSK) protein expression following ACK2 incubation. Western blot analysis and real-time quantitative RT-PCR revealed an apparent time-dependent reduction in Bcl-2 protein levels with respect to ACK2 within the NCCmelb4 cells. In terms of Bax expression, a difference was not found. Fas and caspase8 proteins increased time-dependently in proportion to ACK2 incubation. We noted apoptotic cell death upon addition of ACK2, with evidence of possible involvement of Bcl-2 and Fas in the induction of apoptosis. In contrast, no significant correlation between Fas ligand (Fas-L) expression and ACK2 was found. Fas activation appears to occur independent of Fas-L during ACK2-induced cell death. Therefore, we propose that Fas-L expression in NCCmelb4 cells does not play a major role in facilitating apoptosis. Furthermore, we hypothesize that these molecules combined with SCF/KIT play an important role in regulating the induction of vertebrate NCC apoptosis during embryogenesis.
J Invest Dermatol 2005 Jan
PMID:Bcl-2 reduced and fas activated by the inhibition of stem cell factor/KIT signaling in murine melanocyte precursors. 1565 78

Normal melanocytes require growth support provided by the adjacent basement membrane. In contrast, nevus cells and melanoma cells survive in the dermis, and in vitro on a soft collagen gel. Transforming growth factor-beta1 (TGF-beta1) produced by melanocytes themselves induces apoptosis in normal melanocytes cultured on collagen gel, an effect that can be counteracted by fibroblast growth factor-2 (FGF-2). The purpose of this study was to investigate the mechanisms by which FGF-2 counteracts the apoptotic signals from TGF-beta1 in melanocytes cultured on collagen gel. We report that FGF-2 did not interfere with the signal transduction from the TGF-beta1 receptors to SMAD2/3 proteins. Instead, TGF-beta1 decreased the level of Bcl-2 in normal melanocytes cultured on collagen gel, and FGF-2 reversed the TGF-beta1-mediated reduction in the level of Bcl-2. In nevus and melanoma cells, TGF-beta1 was unable to induce a decrease in the level of Bcl-2, and treatment with FGF-2 did not cause an increase in the level of Bcl-2 in nevus or melanoma cells. In conclusion, our results suggest that a reduction in the level of the anti-apoptotic Bcl-2 is involved in the execution of apoptosis induced by TGF-beta1 in normal melanocytes cultured on collagen gel and that FGF-2 can prevent TGF-beta1 from causing this reduction.
Exp Dermatol 2005 Mar
PMID:FGF-2 blocks TGF-beta1-mediated suppression of Bcl-2 in normal melanocytes. 1574 May 93

Two antibodies, BT14 and L101, detect a tumor-associated cell surface glycoprotein (gp130) whose properties in normal and diseased skin were assessed, and whose molecular identity was determined in this study. In normal skin, gp130 was constitutively expressed on dermal blood vessels and epidermal appendages, but not in interfollicular epidermis. Marked induction was detected within benign and malignant tumors of various origins including viral warts, basal cell carcinomas, squamous cell carcinomas, metastatic melanomas, and cutaneous T cell lymphomas. In vitro studies confirmed the general upregulation of gp130 expression in malignantly transformed cells. Surprisingly, gp130 was also induced in inflammatory skin diseases including psoriasis and allergic contact dermatitis. Halting proliferation of transformed keratinocytes through cytostatic drugs or increasing the Ca2+ concentration in the medium resulted in increased gp130 expression. In addition, overexpression of Bcl-2 led to upregulation of gp130. When the protein was purified and analyzed by peptide mass fingerprinting, we could demonstrate that it is MUC18 (Mel-CAM, CD146). Sequential immunoprecipitations and western blot analyses confirmed the identity of the antigen. Thus, both expression pattern and regulation characteristics of the now-known glycoprotein gp130 extended beyond previously published data regarding MUC18, thus shedding some new light on a supposedly well-known antigen.
J Invest Dermatol 2005 Aug
PMID:Expression of gp130 in tumors and inflammatory disorders of the skin: formal proof of its identity as CD146 (MUC18, Mel-CAM). 1609 47

Terminally differentiated keratinocytes are dead enucleated squams. We showed previously that the mitochondria-dependent cell death pathway might be gradually activated as differentiation progresses. In this study, we demonstrated that protoporphyrin IX, staurosporine, and rotenone induced apoptotic-like changes in the mitochondria, and early differentiation of keratinocytes without inducing apoptosis. Kinetics studies established that differentiation-related changes, including growth arrest, flattened morphology, stratification, and keratin 10 (K10) expression, were downstream of mitochondrial depolarization and proliferation, reactive oxygen species (ROS) production, and release of cytochrome c and apoptosis-inducing factor. When these changes were prevented by overexpressing Bcl-2 or pharmacologically decreasing the ROS level, K10 upregulation was inhibited, implying that the differentiated phenotype and K10 expression require apoptotic mitochondria, ROS being the most likely differentiation-mediating factor. Our data also suggest that the same mitochondria-affecting stimuli can induce either differentiation or apoptosis, depending on the keratinocyte's competency to undergo differentiation, a competency that may be controlled by Bcl-2.
J Invest Dermatol 2005 Oct
PMID:Induction of apoptosis-like mitochondrial impairment triggers antioxidant and Bcl-2-dependent keratinocyte differentiation. 1618 62

We report a 75-year-old Japanese woman with classic Kaposi's sarcoma. PCR amplified human herpesvirus 8 (HHV-8) DNA sequences from her skin lesions and peripheral blood mononuclear cells (PBMC), but not her plasma, saliva or urine. An antibody test against HHV-8 lytic antigens was positive. Immunohistochemical staining detected latent antigen. There was no evidence of HHV-8 infection in her husband, sister or daughter. Genes coding for HHV-8-encoded viral interleukin-6, viral macrophage inflammatory protein I, viral G protein-coupled receptor, viral cyclin D and viral Bcl-2 were expressed to the same degree in both her skin lesion and PBMC. Latency-associated T0.7 mRNA and HHV-8-encoded viral tegument protein genes were expressed in her PBMC at levels lower than in the skin lesions. Based on the gene expression profile, we concluded that lytic HHV-8 infection was present in her skin lesions and PBMC.
Clin Exp Dermatol 2006 Jan
PMID:Transcripts of the human herpesvirus 8 genome in skin lesions and peripheral blood mononuclear cells of a patient with classic Kaposi's sarcoma. 1630 2

Melanin synthesis in the hair follicle (HF) is strictly coupled to the growth stage of the hair cycle and is interrupted during follicle regression (catagen) and resting. Using tyrosine-related protein 2 (Trp)2-LacZ transgenic mice as a model, we show that distinct melanocyte subpopulations of the HF display distinct patterns of apoptosis and survival during catagen. Melanocytes located in the outer root sheath express Bcl-2 and are TUNEL-negative. Part of the pigment-producing melanocytes located above the follicular papilla expresses Fas, TUNEL, and is likely to undergo apoptosis, whereas the other part of these melanocytes expresses c-kit, Bcl-2, and becomes visible in the follicular papilla. During late catagen, TUNEL and Ki-67 negative melanocytes expressing Bcl-2 are seen in the secondary germ of the HF. Lack of proliferation in the follicular melanocytes during catagen suggests that secondary hair germ of late catagen HF is most likely repopulated by melanocytes arising from the outer root sheath or follicular papilla of early/mid-catagen HF. Taken together, these data suggest a possible scenario and mechanisms of the remodeling of the follicular pigmentary unit during HF anagen-catagen-telogen transition and may be used for the establishing in vivo models for pharmacological modulation of melanocyte apoptosis and survival during the hair cycle.
J Invest Dermatol 2005 Dec
PMID:Changes in different melanocyte populations during hair follicle involution (catagen). 1635 97

Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-Nle-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.
J Investig Dermatol Symp Proc 2005 Nov
PMID:Notch and NOXA-related pathways in melanoma cells. 1636 61

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. All three PPAR subtypes, PPAR-alpha, PPAR-beta/delta and PPAR-gamma are expressed in human melanocytes. In this study, we investigated the effects of PPAR-gamma activator on melanocyte growth, and apoptosis. The PPAR-gamma activators ciglitazone, troglitazone, and 15-deoxy-prostaglandin J2 inhibited melanocyte growth in a dose-dependent manner. This inhibitory effect of ciglitazone seemed to occur through induction of apoptosis. Apoptosis was increased after ciglitazone treatment, which was observed by the TUNEL method and flow cytometry. We noted a decrease in extracellular signal regulated kinase protein expression under ciglitazone treatment. Western blot analysis revealed an apparent time-dependent reduction in Bcl-2 protein levels in ciglitazone-treated melanocytes. In terms of Bax expression, a difference was not found. The expression of caspase-3 proteins was increased time-dependently with ciglitazone treatment. These results indicate that melanocyte growth and apoptosis may be modulated through PPAR-gamma and that ciglitazone, a PPAR-gamma activator, inhibits growth of human melanocytes by inducing apoptosis.
Arch Dermatol Res 2006 Apr
PMID:Peroxisome proliferator-activated receptors-gamma activator, ciglitazone, inhibits human melanocyte growth through induction of apoptosis. 1647 74


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