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)

The spectrum of CD30+ cutaneous lymphoproliferative disorders is characterized by the histology of a high-grade lymphoma but frequent clinical regression of skin lesions in lymphomatoid papulosis (LyP) and occasional regression in CD30+ large cell lymphomas (LCLs). A recent study shows that apoptosis may be a significant mechanism of regression of LyP (Arch Dermatol 133:828-833, 1997). Therefore, we studied expression of proteins that induce apoptosis, including CD27, CD40, CD95, and nerve growth factor receptor (NGF-R), as well as anti-apoptotic protein bcl-2 in skin lesions from 25 patients within the spectrum of CD30+ cutaneous lymphoma. Our results show consistent expression of CD95 (APO-1/Fas), but rare or absent expression of CD27, CD40, and NGF-R on tumor cells from both regressing LyP lesions and nonregressing CD30+ lymphomas. Bcl-2 was expressed at low levels in LyP and at high levels in pleomorphic CD30+ lymphomas. These results indicate that, in addition to CD30, CD95 expression is preferentially expressed at high levels in all cutaneous CD30+ lymphomas and suggest that CD95 may play a role in the regression of CD30+ skin lesions. Expression of bcl-2 appears to protect tumor cells from apoptosis in CD30+ lymphoproliferative disorders.
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PMID:Cutaneous CD30+ lymphoproliferative disorders: expression of bcl-2 and proteins of the tumor necrosis factor receptor superfamily. 982 99

Previous models of cutaneous carcinogenesis have primarily focused on the regulation of keratinocyte (KC) proliferation and differentiation. However, it has become clear in many neoplastic systems that altered rates of cell death and/or inability to undergo growth arrest can also contribute to the development of cancer. Apoptosis-regulatory proteins include those that block apoptosis such as Bcl-2 and Bcl-x, whilst a related protein Bax promotes apoptosis. Cell cycle regulatory proteins include those associated with growth arrest, i.e. p21wafl, p53, and those associated with proliferation, i.e. Ki-67. Paraffin embedded samples from ten different lesions of squamous cell carcinoma (SCC), Bowen's disease (BD), keratoacanthomas (KA), and nine normal adult skin samples were stained by immunohistochemistry to detect expression of Bcl-2, Bcl-x, Bax, Ki-67, p21wafl, p53 and apoptosis (TUNEL assay). Compared to low levels of Bcl-x and Bcl-2 immunostaining in normal skin, all the squamoproliferative lesions had strong and diffuse KC expression of Bcl-x (>80%) but minimal to absent KC Bcl-2 expression (<15%). Bax immunopositivity was limited to the basal layer in normal skin and BD. In contrast, by examining serial sections both Bcl-x and Bax appeared to be coexpressed by the majority of malignant KCs in KA and SCC (>70%). These immunostaining profiles reveal that squamoproliferative lesions, including invasive transformed KCs, preferentially express Bcl-x over Bcl-2, in addition to upregulating their Bax levels. Even though there were numerous TUNEL positive cells in these squamoproliferative lesions, no other evidence of apoptosis was seen reinforcing the necessity to use caution when relying on TUNEL staining for identification of programmed cell death in skin biopsies. Normal sun-exposed skin had low but detectable p53 and rare p21wafl KC expression. Significantly higher numbers of p21wafl and p53 immunopositive KCs were noted throughout the lesions in BD and SCC in contrast to KA where p53 and rare p21wafl immunopositive KCs were primarily limited to the periphery of the tumor cell islands. In general, p53 KC expression was higher in all squamoproliferative lesions and sun-exposed normal skin compared to p21Wafl expression. Summary of the expression of cell cycle regulatory proteins for both p21wafl and p53 KC expression was: SCC > BD > KA, in marked contrast to Ki-67 KC expression which was: BD > KA > SCC. The relatively few malignant cells in SCC that were actively participating in the cell cycle (i.e. Ki-67 positive) suggests that these neoplasms may arise primarily by increased cell survival and resistance to apoptosis rather than by hyperproliferation. These studies emphasize the importance of examining multiple members of protein families that regulate apoptosis, proliferation, growth arrest, and differentiation. It is the overall balance between these cellular phenomena that determine whether a cell remains viable or undergoes programmed cell death and contributes to the appearance of a neoplasm. The overexpression of Bcl-x may confer a survival advantage to malignant KCs unable to growth arrest to repair damaged DNA (mutant p53) and/or undergo terminal differentiation (increased p21wafl). Thus, mutation or aberrant expression of such proteins may participate in the multistep process of carcinogenesis that gives rise to these squamoproliferative lesions.
J Dermatol Sci 1999 Jan
PMID:Differential expression of cell survival and cell cycle regulatory proteins in cutaneous squamoproliferative lesions. 989 Mar 76

The epidermal growth factor receptor has multiple roles in epidermal biology relating to growth, migration, and, as shown recently, survival of keratinocytes. In cultured keratinocytes activation of the epidermal growth factor receptor upregulates expression of Bcl-x(L), an anti-apoptotic Bcl-2 homolog. The functional contribution of epidermal growth factor receptor-dependent Bcl-x(L) expression to keratinocyte survival is poorly understood. Here we demonstrate that inhibition of the epidermal growth factor receptor tyrosine kinase activity with either an epidermal growth factor receptor antagonistic monoclonal antibody (MoAb 425) or an epidermal growth factor receptor-selective tyrosine kinase inhibitor (AG 1478) downregulated Bcl-x(L) expression in normal human keratinocytes but had no effect on expression of the pro-apoptotic Bcl-2 homologs Bad, Bak, and Bax. Bovine pituitary extract and insulin partially alleviated both, downregulation of Bcl-x(L) expression and cell death upon epidermal growth factor receptor inhibition. Forced expression of Bcl-x(L) attenuated cell death of immortalized keratinocytes (HaCaT) induced by either forced suspension (anoikis) or by epidermal growth factor receptor blockade. These results demonstrate that epidermal growth factor receptor-dependent signaling pathways control the balance of pro-apoptotic and anti-apoptotic Bcl-2 family members expressed in normal keratinocytes. Inappropriate survival supported by aberrant signaling through the epidermal growth factor receptor may contribute to the pathogenesis of psoriasis and of squamous cell carcinomas.
J Invest Dermatol 1999 Apr
PMID:A central role of Bcl-X(L) in the regulation of keratinocyte survival by autocrine EGFR ligands. 1020 27

Bcl-2 and its homologous proteins play an important role in the control of apoptosis, mainly at the level of mitochondria. Their relationship to differentiation as well as regulation by retinoids in certain cell types has been recently reported. We examined the expression of the bcl-2 family oncoproteins bax, bak, bcl-2, bcl-xL, and mcl-1 in the course of differentiation of human keratinocytes cultured at low- (0.15 mM) and high- (1.87 mM) calcium concentrations. The pro-apoptotic bax showed an increase in expression during the first six days of culture, whereas bak remained stable until day 10 when it increased only slightly in both low- and high-calcium treated cells. The expression of anti-apoptotic bcl-xL increased during the first four days of culture, with a more pronounced increase in low- than in high-calcium treated keratinocytes. Apoptosis-suppressing bcl-2 and mcl-1 proteins did not change significantly in our culture experiment. None of the examined proteins of the bcl-2 family appeared altered upon addition of all-trans retinoic acid (10(-6) M) to the culture medium. We compare the results of our in vitro study with the expression of the bcl-2 family proteins in normal epidermis.
Eur J Dermatol
PMID:Expression of the bcl-2 family of genes in the course of keratinocyte differentiation. 1021 Jul 83

Recently, the proto-oncogenes bcl-2 and bax have emerged as important regulators of the apoptotic form of cell death. We examined UV irradiation-elicited apoptosis and regulation of bcl-2 and bax expression both in vivo in human skin and in vitro in HeLa cells. Using flow cytometric analysis, HeLa cells were found to undergo apoptosis at the 12-h time-point after exposure to UVB irradiation (100 mJ/cm2). The expression of bcl-2 mRNA was found to decrease after a single dose of UVB radiation (doses 10-200 mJ/cm2). In contrast, the expression of bax mRNA was not significantly changed. When human skin was irradiated with a single dose of solar-simulated radiation (40 mJ/cm2), Bcl-2-positive cells were significantly reduced in the epidermis at the 3- and 6-h time-points. Our results suggest that UV irradiation downregulates bcl-2 expression both in vitro at the mRNA level and in vivo at the protein level, and that downregulation of bcl-2 constitutes a mechanism of potential importance in UV-induced apoptosis in human epidermis.
Arch Dermatol Res 1999 Apr
PMID:UV irradiation induces downregulation of bcl-2 expression in vitro and in vivo. 1033 18

Apoptosis plays an important part as a defence mechanism in eliminating damaged cells. Among the complex factors which regulate apoptosis, the p53 tumour suppressor protein which is induced by DNA damage has been suggested to play a crucial part. Cells from xeroderma pigmentosum (XP) patients, which are defective in nucleotide excision repair, express higher levels of p53 and are highly susceptible to cell death after ultraviolet (UV) irradiation. To examine the relationships between DNA damage, p53 and apoptosis, normal and XP group A fibroblasts were exposed to UVB, and expressions of molecules involved in apoptosis were examined. Apoptosis of XP and normal cells was clearly detected at 48 h after irradiation with UVB at doses of 5 and 40 mJ/cm2, respectively. Cells were positive by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) staining under these exposure conditions. At 6 h after irradiation, p53 protein expression was induced in normal and XP cells at minimal doses of 10 and 2.5 mJ/cm2, respectively. Bcl-2 protein, an inhibitor of apoptosis, was downregulated prior to cell death following UVB exposure at doses that induced apoptosis in both cell types. These results suggest that DNA damage due to UVB induces apoptosis by upregulating proapoptotic molecules such as p53, and by downregulating anti-apoptotic molecules such as Bcl-2.
Br J Dermatol 1999 Jun
PMID:Higher susceptibility to apoptosis following ultraviolet B irradiation of xeroderma pigmentosum fibroblasts is accompanied by upregulation of p53 and downregulation of bcl-2. 1035 67

In multicellular organisms, homeostasis is maintained by a balance between cell proliferation and cell death. Two common forms of cell death, called apoptosis and necrosis, have been described. Apoptosis, which is often equated with programmed cell death, is a physiological form of cell death that is responsible for the deletion of cells. Apoptosis is morphologically and biochemically characterized by cell shrinkage, dense chromatin condensation, cellular budding, fragmentation, rapid phagocytosis by nearby cells, and DNA fragmentation into units of approximately 200 base pairs. Apoptosis can be triggered by a wide variety of stimuli such as cytokines, hormones, drugs, and viruses, and their signal transduction tightly regulated by genes such as Bcl-2. Effector caspases are finally activated, resulting in apoptotic cell death. In the skin, there is considerable evidence that apoptosis plays an important role in the pathogenesis of a wide variety of skin diseases. In lichenoid tissue reactions, the Civatte body or colloid body is a form of apoptotic keratinocytes which is mediated by T lymphocytes via Fas-FasL interaction or through the perforin-granzyme B pathway. In several skin tumors, Bcl-2 or FasL expression is involved in the proliferation or regression of the tumors, or in the escape from immune attack by T cells. Moreover, apoptosis is also responsible for the homeostasis of skin, such as the keratinocyte differentiation and hair cycle. In this review, we describe the basic concept of apoptosis and its relevance to skin diseases.
Eur J Dermatol
PMID:Apoptosis and the skin. 1041 50

Keloids and hypertrophic scars represent a model of altered wound healing characterized by overproduction of extracellular matrix and dermal fibroblasts with high mitotic rate. Alteration of apoptosis and cell proliferation has been implicated in the etiology of keloids. The bcl-2 protooncogene encodes a protein that protects cells from programmed cell death while p53 protein functions as negative regulator of cell proliferation. Both protooncogenes have been shown to play a role in tissue homeostasis as apoptotic regulatory genes. The c-jun and c-fos protooncogenes are transactivating factors also involved in fibroblast proliferation. In our study we investigated, by immunohistochemistry, skin specimens from three clinically active hypertrophic scars and keloids, two resting keloids and two early phase morphea to detect both bcl-2 and p53 protein expression, in order to evaluate these apoptotic regulatory genes in different fibrotic conditions. The c-jun and c-fos, at protein and mRNA level, and Ki67 nuclear antigen expression were also investigated. In hypertrophic scars and active keloids we could detect intense Bcl-2 staining in basal keratinocytes and in scattered fibroblast-like and perivascular spindle-shaped cells, while no p53 expression could be demonstrated. The c-jun and c-fos mRNA and protein expression was mainly found in dermal fibroblast-like cells and elongated perivascular cells in all skin biopsies, and similar immunostaining pattern was observed for Ki67 antigen. No protooncogene expression in morphea patients and normal skin, unless Bcl-2 staining in the basal layer of normal epidermis, was documented. Our results suggest that Bcl-2, c-jun and c-fos protein expression and lack of p53 detection in fibroblast-like and perivascular spindle cells are related to increased fibroblast proliferation, confirmed by Ki67 positivity, probably due to alteration of these regulatory apoptotic genes resulting in pathological scarring.
J Dermatol Sci 1999 Dec
PMID:Expression of Bcl-2, p53, c-jun and c-fos protooncogenes in keloids and hypertrophic scars. 1065 Dec 27

Congenital atrichia is a form of total alopecia inherited in an autosomal recessive pattern. In individuals affected with this form of hair loss, hairs are typically absent from the scalp, and patients are nearly completely devoid of eyebrows, eyelashes, axillary and pubic hair, following shedding of the natural hair shortly after birth. We have recently linked this disorder to the chromosomal region 8p12, and cloned the human hairless gene, which resides within this interval. We have identified several mutations in the hairless gene in atrichia families from around the world. In hairless mice, the hair matrix cells appear to undergo a premature and massive apoptosis, together with a concomitant decline in Bcl-2 expression, a loss of NCAM positivity, and a disconnection with the overlying epithelial sheath essential for the movement of the dermal papilla. As a consequence, the hair bulb and dermal papilla remain stranded in the dermis, and indispensible messages between the dermal papilla and stem cells in the bulge are not transmitted, so no further hair growth occurs. These findings suggest that the hairless gene product may play a crucial role in maintaining the delicate balance between cell proliferation, differentiation and apoptosis in the hair follicle, as well as in the interfollicular epidermis.
J Investig Dermatol Symp Proc 1999 Dec
PMID:The molecular basis of congenital atrichia in humans and mice: mutations in the hairless gene. 1067 75

Hair follicle (HF) morphogenesis and cycling are characterized by a tightly controlled balance of proliferation, differentiation and apoptosis. The members of the bcl-2 family of proto-oncogenes are important key players in the apoptosis control machinery of most cell types. Bcl-2, an apoptosis inhibitor, and Bax, an apoptosis promoter, show tightly regulated, hair cycle-dependent expression patterns: during catagen, the distal ORS of the HF remains strongly positive for Bcl-2 and Bax; in contrast, the proximal epithelial part of the HF loses most Bcl-2 expression while it remains strongly positive for Bax. In Bcl-2 null mice, skin becomes markedly hypopigmented during the first postnatal anagen probably due to increased melanocyte apoptosis. Reportedly, these mice also show a retardation of the first anagen development after birth. Transgenic mice overexpressing Bcl-2 under the control of the keratin-1 promoter display multifocal epidermal hyperplasia and aberrant expression of keratin-6, while alterations of HF cycling have not been investigated. Surprisingly, Bcl-2 overexpression under the control of the keratin-14 promoter leads to accelerated catagen progression and increased chemotherapy-induced apoptosis, HF dystrophy and alopecia. Transgenic mice overexpressing Bcl-X(L), another anti-apoptotic bcl-2 family member, under the control of the K14 promoter, reportedly also display accelerated catagen development. These and other Bcl-2 transgenic and null mice are now available to further dissect the as yet unclear, and likely complex, role of Bcl-2 in HF growth and pigmentation.
J Investig Dermatol Symp Proc 1999 Dec
PMID:Hair follicle apoptosis and Bcl-2. 1067 80


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