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 maintenance of homeostasis in normal tissues reflects a balance between cell proliferation and cell death. Bcl-2 inaugurated a new category of oncogenes, regulators of cell death. The Bcl-2 gene was identified at the chromosomal breakpoint of t(14;18) bearing B cell lymphomas. Bcl-2 proved unique by blocking programmed cell death rather than promoting proliferation. In adults, Bcl-2 is topographically restricted to progenitor cells and longlived cells but is much more widespread in the developing embryo. Transgenic mice that overexpress Bcl-2 demonstrate extended cell survival, and progress to high grade lymphomas. Bcl-2 has been localized to mitochondria, endoplasmic reticulum and nuclear membranes, also the sites of reactive oxygen species generation. Bcl-2 does not appear to influence the generation of oxygen free radicals but does prevent oxidative damage to cellular constituents including lipid membranes. Bcl-2 deficient mice complete embryonic development but undergo fulminant lymphoid apoptosis of thymus and spleen. Moreover, they demonstrate two unexpected pathologies resulting from cell death, polycystic kidney disease and hair hypopigmentation. The latter is a potential oxidant injury from the melanin biosynthetic pathway. A family of Bcl-2 related genes is emerging that includes Bax, a conserved homolog that heterodimerizes in vivo with Bcl-2 and promotes cell death. The ratio of family members, such as Bcl-2/Bax, determines the survival or death of cells following an apoptotic stimulus.
 ...
PMID:Reactive oxygen species and the regulation of cell death by the Bcl-2 gene family. 759 27

Transgenic mice homozygously lacking in the bcl-2 gene were generated using homologous recombination in embryonal stem cells. The complete absence of Bcl-2 alpha and -beta proteins did not interfere with normal embryonic development. Abnormalities became evident after birth, although the severity varied among homozygous null mice, bcl-2-/- mice displayed pleiotropic abnormalities similar to those in the previously described bcl-2-/- mice, including growth retardation, smaller ears, short lives, polycystic kidney, atrophic thymus and spleen with accelerated apoptotic cell death of lymphocytes, and hair hypopigmentation in the second hair follicle cycle. Our bcl-2-/- mice also revealed novel defects in the small intestine, characterized by retarded development, accelerated exfoliation of epithelial cells, and very few mitotic progenitor cells.
 ...
PMID:bcl-2 deficiency in mice leads to pleiotropic abnormalities: accelerated lymphoid cell death in thymus and spleen, polycystic kidney, hair hypopigmentation, and distorted small intestine. 781 68

The maintenance of homeostasis in normal tissues reflects a balance between cell proliferation and cell death. The importance of both positive and negative regulators of cell growth has been well documented in neoplasia. Bcl-2 argues for the existence of a new category of oncogenes, regulators of cell death. The bcl-2 gene was identified at the chromosomal breakpoint of t(14; 18) bearing B cell lymphomas. Bcl-2 has proved to be unique among protooncogenes in blocking programmed cell death rather than promoting proliferation. In adults, bcl-2 is topographically restricted to progenitor cells and longlived cells but is much more widespread in the developing embryo. Transgenic mice that overexpress bcl-2 in the B cell lineage demonstrate extended cell survival, and progress to high grade lymphomas. Bcl-2 has been localized to mitochondria, endoplasmic reticulum and nuclear membranes, also the sites of reactive oxygen species generation. Bcl-2 does not appear to influence the generation of oxygen free radicals but does prevent oxidative damage to cellular constituents including lipid membranes. Bcl-2 deficient mice complete embryonic development and display relatively normal haematopoietic differentiation but undergo fulminant lymphoid apoptosis of thymus and spleen. Moreover, they demonstrate two potentially oxidation related pathologies: polycystic kidney disease and hair hypopigmentation. A family of bcl-2 related genes is emerging that includes Bax, a conserved homolog that heterodimerizes in vivo with bcl-2. A pre-set ratio of Bcl-2/Bax appears to determine the survival or death of cells following an apoptotic stimulus.
 ...
PMID:Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. 814 17

Mice carrying ablated coding regions of the bcl-2 alpha and bcl-2 beta transcripts have been made. bcl-2-/- mutants are smaller but viable, although about half of them die by 6 weeks of age. As shown earlier with somatic bcl-2 gene-targeted mice, the number of lymphocytes markedly decreased within few weeks after birth while other hematopoietic lineages remained unaffected. Among lymphocytes, CD8+ T cells disappeared most quickly followed by CD4+ T cells, whereas B cells were least affected. bcl-2-/- lymphocytes, however, could respond normally to various stimuli including anti-CD3, Con A, phorbol 12-myristate 13-acetate plus ionomycin, interleukin 2, lipopolysaccharide, and anti-IgM antibody. Abnormalities among nonlymphoid organs include smaller auricles, hair color turning gray at 4-5 weeks of age, and polycystic kidney disease-like change of renal tubules. These results suggest that Bcl-2 may be involved during morphogenesis where inductive interactions between epithelium and mesenchyme are important such as in the kidneys, hair follicles, and perichondrium of auricles. Surprisingly, the nervous system, intestines, and skin appear normal despite the fact that these organs show high levels of endogenous Bcl-2 expression in normal mice.
 ...
PMID:Targeted disruption of Bcl-2 alpha beta in mice: occurrence of gray hair, polycystic kidney disease, and lymphocytopenia. 817 Sep 72

bcl-2-/-mice complete embryonic development, but display growth retardation and early mortality postnatally. Hematopoiesis including lymphocyte differentiation is initially normal, but thymus and spleen undergo massive apoptotic involution. Thymocytes require an apoptotic signal to manifest accelerated cell death. Renal failure results from severe polycystic kidney disease characterized by dilated proximal and distal tubular segments and hyperproliferation of epithelium and interstitium. bcl-2-/-mice turn gray with the second hair follicle cycle, implicating a defect in redox-regulated melanin synthesis. The abnormalities in these loss of function mice argue that Bcl-2 is a death repressor molecule functioning in an antioxidant pathway.
 ...
PMID:Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. 840 9

In adult multicellular organisms, homeostasis is determined in each cell lineage by a balance between cell death and cell growth. Dysregulation of cell death mechanisms is involved in the pathogenesis of an increasing number of diseases. Defective apoptosis can participate in malignant transformation, viral latency and autoimmune diseases. Excessive apoptotic cell death is involved in CD4+ T-cell depletion observed in acquired immune deficiency syndrome, in fulminant hepatitis associated with infection by hepatitis B and C viruses, in some neurodegenerative disorders and haematological diseases, in polycystic kidney disease and ischaemia. Three steps can be distinguished in the pathway that leads to cell death. The first step involves interactions between the extracellular and intracellular signals that decide whether a cell should live or die. When death is chosen, a common pathway that involves at least the Bcl-2- family of proteins and the interleukin-1 beta (IL-1 beta)-converting enzyme-related cysteine proteases confirms whether or not the cell should die. Finally, if death is allowed to occur, the apoptotic process itself is characterized by deoxyribonucleic acid (DNA) fragmentation, proteolysis and morphological changes that precede the engulfment of apoptotic cells by neighbouring cells and phagocytes. Several inducers and inhibitors of apoptosis acting on one or several of these three steps that characterize the apoptotic process have been identified in vitro. Their potential usefulness in improving the current therapeutic strategies and designing new strategies in several different diseases is discussed.
 ...
PMID:The role of apoptosis in the pathogenesis and treatment of diseases. 880 51

The proto-oncogene c-myc has been implicated in both cellular proliferation and apoptosis, and we have shown that overexpression of c-myc can induce polycystic kidney disease in transgenic mice. To elucidate the molecular and cellular defects underlying cystogenesis, we have investigated the potential roles of cell proliferation and apoptosis as they relate to c-myc and modulators of c-myc function in human autosomal dominant polycystic kidney disease (ADPKD). Renal c-myc expression was consistently elevated, up to 15-fold, in ADPKD. High levels of c-myc expression correlated with 10- to 100-fold increased proliferation index in cystic epithelium. Interestingly, steady-state levels of bcl-2 mRNA were also increased up to 20-fold and Bcl-2 protein was markedly elevated. In contrast, the expression of bax and p53 was virtually unchanged. However, apoptosis was consistently and significantly increased in ADPKD kidneys, unchecked by high levels of Bcl-2. Together with proliferation, apoptosis may thus represent a general mechanism for cyst growth and tissue remodeling. We conclude that both epithelial cell proliferation and apoptosis required for normal kidney homeostasis are deregulated in ADPKD, recapitulating the renal developmental program. Furthermore, abnormal expression of proto-oncogenes regulating these processes is an important mediator of cystogenesis in human ADPKD.
 ...
PMID:Dysregulation of cellular proliferation and apoptosis mediates human autosomal dominant polycystic kidney disease (ADPKD). 880 89

While generating bcl2 alpha transgenic mice, we found some F2 offspring of one of the transgenic lines which were very small and had closed eyes at the time of weaning. These pups died within 1 month after birth. In order to determine the molecular basis of this phenotype, we screened a genomic library of the above transgenic line with a transgene-specific probe and found that the Bmp7 gene, a member of the TGF beta superfamily, was inactivated by insertional mutagenesis due to transgene integration. The Bmp7 homozygous null condition in mice is a postnatal lethal mutation and is associated with various developmental defects: holes in the basisphenoid bone and the xyphoid cartilage, retarded ossification of bones, fused ribs and vertebrae, underdeveloped neural arches of the lumbar and sacral vertebrae, polydactyly of the hind limbs, a kinked tail, a reduced number of nephrons, polycystic kidney, lack of retinal pigmentation, and retarded lens development. These findings indicate that BMP7 is an important signaling molecule for normal development of the mammalian skeleton, kidney, and eye. Academic Press
 ...
PMID:BMP7 null mutation in mice: developmental defects in skeleton, kidney, and eye. 901 3

Apoptosis is triggered when proapoptotic members of the Bcl-2 protein family bearing only the BH3 association domain bind to Bcl-2 or its homologs and block their antiapoptotic activity. To test whether loss of the BH3-only protein Bim could prevent the cellular attrition caused by Bcl-2 deficiency, we generated mice lacking both genes. Mice without Bcl-2 have a fragile lymphoid system, become runted, turn gray, and succumb to polycystic kidney disease. Concomitant absence of Bim prevented all these disorders. Indeed, loss of even one bim allele restored normal kidney development, growth, and health. These results demonstrate that Bim levels set the threshold for initiation of apoptosis in several tissues and suggest that degenerative diseases might be alleviated by blocking BH3-only proteins.
 ...
PMID:Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim. 1170 85

Apoptosis is a critical early cellular event in the development of polycystic kidney disease (PKD) in humans and mice. In the SBM transgenic model of PKD, both apoptosis and proliferation are c-myc driven and are independent of p53 and Bcl-2 pathways. On the basis of recent evidence implicating the FasL/Fas pathway in c-myc-induced apoptosis, we investigated the potential interaction of these pathways in vivo. We first evaluated the expression of FasL in renal tissues of SBM mice. This analysis showed that the level of FasL expression was elevated 3-4-fold in the SBM kidneys, indicating a potential autocrine suicidal mechanism. We next crossed the SBM mice with gld mice mutated in FasL. The progenies had comparable renal epithelial apoptotic and proliferation rates and a cystic phenotype in all SBM genotypes irrespective of the FasL genotype. Our study proves that c-myc-induced apoptosis can be independent of the FasL/Fas pathway in vivo and implicates the existence of a novel c-myc-driven apoptotic pathway.
 ...
PMID:c-myc-induced apoptosis in polycystic kidney disease is independent of FasL/Fas interaction. 1195 70


1 2 3 Next >>