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)

CD95 (Fas/APO-1) is a cell surface receptor able to trigger apoptosis in a variety of cell types. The expression and function of the CD95 antigen on leukemic blasts from 42 patients with B lineage and 53 patients with T lineage acute lymphoblastic leukemia (ALL) were investigated using immunofluorescence staining and apoptosis assays. The CD95 surface antigen was expressed in most ALL cases, with the T lineage ALL usually showing a higher intensity of surface CD95 expression as compared with the B lineage ALL cells (relative fluorescence intensity, RFI: 4.8 +/- 0.47 vs 2.2 +/- 0.23, respectively, P < 0.01). Functional studies disclosed that upon oligomerization by anti-CD95 monoclonal antibodies the CD95 protein was either not able to initiate apoptosis of leukemic cells (75% of cases) or induced low rates of apoptosis (20% of cases). Only in 5% of cases did the apoptosis rate exceed the 20% level of the CD95-specific apoptosis. Most of the CD95-sensitive cases were found among T lineage ALLs (38% of T lineage vs 10% of B lineage ALLs). Overall, the extent of CD95-induced apoptosis did not correlate with the expression level of CD95. Similarly, no significant correlation between expression level and functionality of CD95 in human leukemia cell lines of B and T cell origin could be observed. Bcl-2 protein has been associated with prolonged cell survival and has been shown to block partially CD95-mediated apoptosis, but for ALL cells no correlation between bcl-2 expression and spontaneous or CD95-mediated apoptosis could be found. The results obtained in this study indicate that, despite constitutive expression of CD95, the ALL cells are mainly resistant to CD95-triggering. More detailed investigations of the molecular mechanisms involved in the intracellular apoptotic signal transduction, such as interactions of the bcl-2 and the other members of the bcl-2 family, and functionality of the interleukin-1beta converting enzyme (ICE) like-proteases, may give new insights into key events responsible for the resistance or sensitivity to the induction of apoptosis in acute leukemia.
Leukemia 1997 Aug
PMID:Differential CD95 expression and function in T and B lineage acute lymphoblastic leukemia cells. 926 77

Release of mitochondrial cytochrome c has been recently linked to the activation of the "executioner" phase of the cellular programs for death by apoptosis. This release is known to be negatively regulated by Bcl-2 and Bcl-XL proteins. We show here that treatment of human leukemia cells HL60 with 1,25-dihydroxyvitamin D3 (1,25D3) results in progressive increases in the levels of cellular antiapoptotic protein Mcl-1, a transient increase in Al protein level, but no increases in Bcl-2 or Bcl-XL proteins. The increase in Mcl-1 protein levels correlates with a reduced extent of apoptotic cell death induced by etoposide or the calcium ionophore A23187. The Mcl-1 protein is primarily localized in the mitochondria, and etoposide- or A23187-induced cytochrome c release is reduced in cells in which the mitochondria contain the Mcl-1 protein demonstrable by immunoblots. Raf-1 protein can also be detected in the mitochondrial fractions that contain Mcl-1 protein but not in the Mcl-1-negative fractions. These findings suggest that in these promyelocytic leukemia cells Mcl-1 has a function analogous to that of Bcl-2 in other cells, i.e., to target Raf-1 to mitochondria and to reduce cell damage-induced release of mitochondrial cytochrome c. Our findings provide a potential mechanism for the antiapoptotic action of 1,25D3 and show that differentiation and apoptosis signaling pathways not only interact but involve a proliferation-associated gene, Raf-1.
 ...
PMID:Antiapoptotic action of 1,25-dihydroxyvitamin D3 is associated with increased mitochondrial MCL-1 and RAF-1 proteins and reduced release of cytochrome c. 928 70

The BCR/ABL oncogenic tyrosine kinase activates phosphatidylinositol 3-kinase (PI-3k) by a mechanism that requires binding of BCR/ABL to p85, the regulatory subunit of PI-3k, and an intact BCR/ABL SH2 domain. SH2 domain BCR/ABL mutants deficient in PI-3k activation failed to stimulate Akt kinase, a recently identified PI-3k downstream effector with oncogenic potential, but did activate p21 RAS and p70 S6 kinase. The PI-3k/Akt pathway is essential for BCR/ABL leukemogenesis as indicated by experiments demonstrating that wortmannin, a PI-3k specific inhibitor at low concentrations, suppressed BCR/ABL-dependent colony formation of murine marrow cells, and that a kinase-deficient Akt mutant with dominant-negative activity inhibited BCR/ABL-dependent transformation of murine bone marrow cells in vitro and suppressed leukemia development in SCID mice. In complementation assays using mouse marrow progenitor cells, the ability of transformation-defective SH2 domain BCR/ABL mutants to induce growth factor-independent colony formation and leukemia in SCID mice was markedly enhanced by expression of constitutively active Akt. In retrovirally infected mouse marrow cells, the BCR/ABL mutant lacking the SH2 domain was unable to upregulate the expression of c-Myc and Bcl-2; in contrast, expression of a constitutively active Akt mutant induced Bcl-2 and c-Myc expression, and stimulated the transcription activation function of c-Myc. Together, these data demonstrate the requirement for the BCR/ABL SH2 domain in PI-3k activation and document the essential role of the PI-3k/Akt pathway in BCR/ABL leukemogenesis.
 ...
PMID:Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. 932 94

Vesnarinone is a positive inotropic agent used for treating congestive heart failure. We evaluated its ex vivo effects on myeloid leukemia cell lines and primary acute myelogenous leukemia cells. Vesnarinone inhibited the incorporation of radiolabeled thymidine by a myeloid cell line, HL60, in a dose-dependent manner at concentrations ranging from 0.1 to 30 microg/mL. A maximum 40% suppression was seen at a concentration of 10 microg/mL. Determination of viable cell counts by trypan blue dye exclusion method demonstrated vesnarinone to be cytocidal for HL60 cells. Vesnarinone induced DNA fragmentation as detected by electrophresis in HL60 cells after 72-hour culture; this effect was not inhibited by G-CSF. The apoptosis induced by vesnarinone was also detected by the in situ end-labeling method. Northern blot analysis showed a reduction of c-myc mRNA expression in HL60 cells by vesnarinone. However, immunostaining assay showed no change in the expression of Fas and Bcl-2 proteins. We next examined the effect of vesnarinone on primary myeloid leukemia cells derived from 10 patients: 3 cases of M1, 2 of M2, 3 of M3, 1 of M4, and 1 of M6, by the French-American-British classification. Vesnarinone inhibited the incorporation of thymidine in all cells, with a mean suppression of 58.1%. DNA electrophoresis showed induction of DNA fragmentation in cultured cells with vesnarinone for 72 hours in 8 of the 10 patients with primary leukemia. However, bone marrow mononuclear cells from healthy controls showed no growth suppression or DNA fragmentation in response to vesnarinone. These results suggest that vesnarinone may be useful in treating myeloid leukemia.
 ...
PMID:Vesnarinone exhibits antitumor effect against myeloid leukemia cells via apoptosis. 932 55

Animal models of motor neurone disease (MND) are being increasingly used for screening molecules with clinical potential. A number of different treatments to decrease the progression of neuronal cell loss have been proposed; these include: Bcl-2 (B-cell leukaemia oncogene-2), neurotrophic factors, glutamate receptor inhibitors and Ca2+ channel antagonists. In this review Yves Sagot, Richard Vejsada and Ann C. Kato focus on the effects of neurotrophic factors and Bcl-2, both of which have been shown to prevent cell death in various experimental paradigms. Studies performed in animal models of MND have confirmed the potential of these molecules to support motoneurone survival. Some of them have been shown to act in synergy and these results are discussed in the context of molecular mechanisms leading to collaborative and synergistic activities, and also with respect to presumptive subpopulations of motoneurones, which express diverse receptors for neurotrophic factors. Finally, the current status of clinical trials for amyotrophic lateral sclerosis using neurotrophic factors will be discussed, as well as recent reports that neurotrophic factors can exert adverse effects on neuronal survival.
 ...
PMID:Clinical and molecular aspects of motoneurone diseases: animal models, neurotrophic factors and Bcl-2 oncoprotein. 934 52

Homeostasis of human B cell development is maintained by a complex network of cytoplasmic and surface expressed molecules. Abnormalities in this process may result in the expansion of malignant B cell precursors in B lineage acute lymphoblastic leukaemia (ALL). ALL cells share surface antigens with normal early precursor B cells. We have studied here the role of Fas/APO-1 (CD95) antigen on leukaemic precursor B cell line growth and survival, and the modulation of its effects by signals involved in normal early B cell development. Four ALL cell lines representative of the early steps of B cell differentiation are shown to express surface Fas/APO-1 (CD95) antigen and to undergo apoptosis in the presence of anti-Fas cross-linking antibodies. This effect is strongly enhanced when pre-B, but not pro-B cells, are pretreated with IL-7 but not with IL-2, IL-3, IL-4 or IL-10. Furthermore, pre-B cell death induced by anti-Fas antibodies in combination with IL-7 is increased upon pre-B receptor but not CD19 cross-linking. Bcl-2 and Bax protein expression is not influenced by IL-7 or pre-BR stimulation in either pro-B or pre-B cell lines. These results indicate that signals involved in normal early B cell development can modulate the Fas (CD95)-mediated apoptosis of leukaemic precursor B cells.
 ...
PMID:IL-7 sensitizes human pre-B cells but not pro-B cells to Fas/APO-1 (CD95)-mediated apoptosis. 936 21

Thioredoxin peroxidase (TPx) is a member of a newly discovered family of proteins that are conserved from yeast to mammals and to which natural killer enhancing factor belongs. These proteins are antioxidants that function as peroxidases only when coupled to a sulfhydryl reducing system. The physiological function of TPx in cells is not yet known. Here we demonstrate that when the human TPx II, a member of this family, is stably overexpressed in Molt-4 leukemia cells, it protects from apoptosis induced by serum deprivation, ceramide, or etoposide. TPx II, like Bcl-2, is able to inhibit release of cytochrome c from mitochondria to cytosol, and it inhibits lipid peroxidation in cells. TPx II, unlike Bcl-2, could prevent hydrogen peroxide accumulation in cells, suggesting that it functions upstream of Bcl-2 in the protection from apoptosis and may be implicated as an endogenous regulator of apoptosis.
 ...
PMID:Thioredoxin peroxidase is a novel inhibitor of apoptosis with a mechanism distinct from that of Bcl-2. 938 94

A case of Hodgkin's disease (HD), lymphocyte depression (LD) type in an immunosuppressive patient is described. The patient was a 48-year-old male and his parents were born in the Kyushu area, which is an endemic area for adult T cell lymphoma/leukemia (ATL). He was seropositive for ATL virus (ATLV, also referred to as HTLV-I) and showed a marked immunosuppressive condition. He developed LD-HD and Pneumocystis carinii pneumonia, and died due to respiratory failure. The immunohistochemical and in situ hybridization analyses revealed that the Reed-Sternberg-like cells in the lymph node biopsy sample were positive for Ber-H2 (CD30), Leu-M1 (CD15), L-26 (CD20), Bcl-2, p53 and EBER, the viral genome of Epstein-Barr virus (EBV).
 ...
PMID:Epstein-Barr virus-related Hodgkin's disease showing B cell lineage in an immunosuppressive patient seropositive for HTLV-I. 941 42

The oxysterols, 7beta-hydroxycholesterol and 7-ketocholesterol, are involved in the cytotoxicity of oxidized LDL. To elucidate their molecular mechanisms, the human promonocytic leukemia cells U937 and U4 were used. U4 cells overexpressing Bcl-2 were obtained by transfection of U937 cells. 7Beta-hydroxycholesterol and 7-ketocholesterol induced nuclear condensation and/or fragmentation, internucleosomal DNA fragmentation, and IL-1beta secretion, which were partially inhibited by Bcl-2 overexpression. These findings underline that these oxysterols could constitute major risk factors in atherosclerosis by their cytotoxicity and their ability to induce IL-1beta release which might favor the recruitment of immunocompetent cells in the atherosclerotic plaque.
 ...
PMID:Induction of apoptosis and of interleukin-1beta secretion by 7beta-hydroxycholesterol and 7-ketocholesterol: partial inhibition by Bcl-2 overexpression. 942 50

Bcl-2, Bcl-xL, and Mcl-1 are three related intracellular polypeptides that have been implicated as negative regulators of apoptosis. In contrast, the partner protein Bax acts as a positive regulator of apoptosis. Based on the observation that all four of these polypeptides are expressed in a variety of acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL) cell lines, cellular levels of these polypeptides were examined by immunoblotting in bone marrow samples harvested from 123 adult AML patients and 36 adult ALL patients before initial antileukemic therapy. Levels of Bcl-2, Mcl-1, Bcl-xL, and Bax each varied over a more than 10-fold range in different pretreatment leukemia specimens. When the 54 AML and 23 ALL samples that contained greater than 80% malignant cells were examined in greater detail, it was observed that pretreatment levels of Bcl-2 and Mcl-1 correlated with each other (R = .44, P < .001 for AML and R = .79, P < .0001 for ALL). In addition, a weak negative correlation between Bax expression and age was observed in AML samples (R = -0.35, P < .02) but not ALL samples. There was no relationship between pretreatment levels of these polypeptides and response to initial therapy. However, examination of 19 paired samples (the first harvested before chemotherapy and the second harvested 23 to 290 days later at the time of leukemic recurrence) revealed a greater than or equal to twofold increase in Mcl-1 levels in 10 of 19 pairs (7 of 15 AML and 3 of 4 ALL) at recurrence. In contrast, 2 of 19 pairs contained twofold less Mcl-1 at the time of recurrence. Approximately equal numbers of samples showed twofold increases and decreases in Bcl-2 (5 increases, 3 decreases) and Bcl-xL (1 increase, 4 decreases) at recurrence. Bax levels did not show a twofold decrease in any patient. these results, coupled with recent observations that cells overexpressing Mcl-1 are resistant to a variety of chemotherapeutic agents, raise the possibility that some chemotherapeutic regimens might select for leukemia cells with elevated levels of this particular apoptosis inhibitor.
 ...
PMID:Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. 944 61


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