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)

Inhibition of the key enzyme in DNA synthesis, thymidylate synthase (TS), by 5-fluorouracil (5-FU) and the novel antifolate raltitrexed (Tomudex; ZD1694), induces dTTP depletion, resulting in DNA strand breaks, which can initiate pathways leading to an apoptotic mode of cell death. We studied 5-FU- and ZD1694-induced TS inhibition in relation to the expression of p53, p21, Bcl-2 and Bax in six colon carcinoma cell lines, two with a wild-type (wt) p53 (Lovo, LS174T) and four with a mutant (mt) p53 (WiDr, WiDr/F, HT29 and SW948) phenotype. In untreated cells, a reciprocal correlation between p53 and Bcl-2 was found: in cells with a low wt p53, Bcl-2 expression was present; whilst in cells with mt p53, Bcl-2 expression was not detectable. Exposure to 5-FU (50 and 100 microM) and ZD1694 (50 and 100 nM) for 24 and 48 h induced p53 and p21 expression in wt p53 cells, but not in mt p53 cells. TS was induced approximately 2-10-fold in all cell lines. TS induction was highest after ZD1694 exposure in the mt p53 cells HT29 and WiDr/F (6-10-fold). After 5-FU treatment, TS was present both as the free enzyme and in the ternary complex; however, predominantly as the ternary complex between TS, FdUMP and 5,10-methylenetetrahydrofolate. In wt p53 cells, both drugs increased Bax expression up to 5-fold, whereas in mt p53 cells, only a very slight induction was found. In wt p53 cells, Bcl-2 expression hardly changed after drug treatment. These results indicate a p53-independent induction of TS but a regulatory role of wt p53 in the synthesis of Bax in the colon carcinoma cell lines after TS inhibition.
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PMID:Molecular downstream events and induction of thymidylate synthase in mutant and wild-type p53 colon cancer cell lines after treatment with 5-fluorouracil and the thymidylate synthase inhibitor raltitrexed. 1078 98

Although carboplatin (CBDCA) has been used for the treatment of several types of tumors, the complete response rate has been limited, probably because of inherent or CBDCA-induced resistance. As a first step to overcome these problems, we tried to elucidate the mechanisms of CBDCA-mediated cytotoxicity in the squamous cell carcinoma cell line MIT7. The treatment of cells with CBDCA resulted in apoptosis in a dose-dependent manner, as assessed by the propidium iodide staining method and DNA degradation in a nucleosomal pattern. The induction of apoptosis was accompanied by the decline of mitochondrial membrane potential (Deltapsi(m) ) at 12 h following CBDCA stimulation. Variant forms of p18 Bax-alpha and p16 Bcl-x(L) were generated with the down-regulation of both Bax-alpha (p21) and Bcl-x(L) (p31) at 36 and 48 h following CBDCA stimulation, suggesting that the modulation of Bcl-2 family proteins Bax-alpha and Bcl-x(L) play some role in CBDCA-mediated apoptosis. The activation of caspase-3 and -8 occurred at 12 and 24 h following the stimulation, respectively. The pretreatment of cells with pan-caspase inhibitor Z-VAD-fmk markedly prevented CBDCA-mediated cytotoxicity/apoptosis and the modulation of Bcl-2 family proteins (generation of p18 Bax-alpha and p16 Bcl-x(L) ) with only slight prevention of decline of Deltapsi(m). Taken together, these results may suggest that activation of several caspases, including caspase-3 and -8, plays some role in CBDCA-mediated apoptosis, probably through the modification of Bcl-2 family proteins, Bax-alpha and Bcl-x(L). Moreover, caspase activation may occur downstream of membrane depolarization.
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PMID:Cleavage of Bax-alpha and Bcl-x(L) during carboplatin-mediated apoptosis in squamous cell carcinoma cell line. 1079 31

The role of Bcl-2 as an anti-apoptotic protein has been well documented. In the present work, we present evidence that Bcl-2 may also be involved in cell growth regulation. SC-M1 is an unique cell line which responds to retinoic acid (RA) treatment with reversible growth arrest [Shyu, Jiang, Huang, Chang, Wu, Roffler and Yeh (1995) Eur. J. Cancer 31, 237-243]. In this study, when treated with RA, SC-M1/Bcl2 cells, which were generated by transfecting SC-M1 cells with bcl-2 DNA, were growth-arrested two days earlier than SC-M1/neo cells, which were generated by transfecting SC-M1 cells with vector DNA. This indicates that Bcl-2 accelerates RA-induced growth arrest. In addition to the accelerated growth arrest, RA-treated SC-M1/Bcl2 cells also recovered from growth arrest two days faster than SC-M1/neo cells after the removal of RA. Previously, we had identified the cyclin-dependent kinase inhibitor p21((WAF1/CIP1)) (p21) as a mediator of RA-induced growth arrest [Tsao, Li, Kuo, Liu and Chen (1996) Biochem. J. 317, 707-711]. In a search for the mechanism by which Bcl-2 affects growth regulation, we found that p21 gene expression was more prominent in SC-M1/Bcl2 cells than in SC-M1/neo cells in the presence of RA, but when RA was removed, p21 gene expression levels in SC-M1/Bcl2 cells were also reduced earlier than in SC-M1/neo cells. The present report is the first to show that Bcl-2 accelerates not only growth arrest but also recovery from growth arrest. Moreover, the close correlation between the effect of Bcl-2 on both RA-induced growth arrest and RA-induced p21 gene expression suggests the possibility that Bcl-2 affects cell growth through the mechanism of p21.
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PMID:Bcl-2 accelerates retinoic acid-induced growth arrest and recovery in human gastric cancer cells. 1081 44

We investigated the in vitro effect of As2O3 on proliferation, cell cycle regulation, and apoptosis in human myeloma cell lines. As2O3 significantly inhibited the proliferation of all of eight myeloma cell lines examined in a dose-dependent manner with IC50 of approximately 1-2 microM. DNA flow cytometric analysis indicated that As2O3 (2 microM) induced a G1 and/or a G2-M phase arrest in these cell lines. To address the mechanism of the antiproliferative effect of As2O3, we examined the effect of As2O3 on cell cycle-related proteins in MC/CAR cells in which both G1 and G2-M phases were arrested. Western blot analysis demonstrated that treatment with As2O3 (2 microM) for 72 h did not change the steady-state levels of CDK2, CDK4, cyclin D1, cyclin E, and cyclin B1 but decreased the levels of CDK6, cdc2, and cyclin A. The mRNA and protein levels of CDKI, p21 were increased by treatment with As2O3, but those of p27 were not. In addition, As2O3 markedly enhanced the binding of p21 with CDK6, cdc2, cyclin E, and cyclin A compared with untreated control cells. Furthermore, the activity of CDK6-associated kinase was reduced in association with hypophosphorylation of Rb protein. The activity of cdc2-associated kinase was decreased, which was accompanied by the up-regulation of cdc2 phosphorylation (cdc2-Tyr15 phosphorylation) resulting from reduction of cdc25B and cdc25C phosphatases. As2O3 also induced apoptosis in MC/CAR cells as evidenced by flow cytometric detection of sub-G1 DNA content and annexin V binding assay. This apoptotic process was associated with down-regulation of Bcl-2, loss of mitochondrial transmembrane potential (delta psi(m)), and an increase of caspase-3 activity. These results suggest that As2O3 inhibits the proliferation of myeloma cells, especially MC/CAR cells, via cell cycle arrest in association with induction of p21 and apoptosis.
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PMID:Arsenic trioxide-mediated growth inhibition in MC/CAR myeloma cells via cell cycle arrest in association with induction of cyclin-dependent kinase inhibitor, p21, and apoptosis. 1085 Apr 58

As the occurrence of structural p53 mutations in hepatocellular carcinoma (HCC) in Thailand was previously reported to be much lower than that found in other high-incidence HCC areas, we analyzed 16 HCC samples from Thailand to determine the expression and functionality of p53 protein. We observed the overexpression of p53 protein in 69% of HCC, despite the prevalence of the wild-type p53 gene. However, the overexpressed p53 protein was nonfunctional as suggested by its inability to modulate the expressions of several p53 effector proteins (p21 and Bcl-2 family proteins). In addition, we observed significant underexpression of two proapoptotic proteins, Bax and Bcl-X(S), in 81% (P = 0.02) and 64% (P = 0.03) of HCC, respectively. Consequently, the ratios of proapoptotic to antiapoptotic BCL-2 family proteins were reduced in 88% of the HCC tumor tissues when compared to normal tissues, such that the rheostat between BCL-2 family proteins is strongly skewed toward enhanced cell survival in the tumor cells.
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PMID:Downregulation of proapoptotic proteins Bax and Bcl-X(S) in p53 overexpressing hepatocellular carcinomas. 1087 63

Brca1 (breast cancerl, early onset) deficiency results in early embryonic lethality. As Brca1 is highly expressed in the T cell lineage, a T cell-specific disruption of Brca1 was generated to assess the role of Brca1 in relation to T lymphocyte development. We found that thymocyte development in Brca1-/- mice was impaired not as a result of V(D)J T cell receptor (TCR) recombination but because thymocytes had increased expression of tumor protein p53. Chromosomal damage accumulation and abnormal cell death were observed in mutant cells. We found that cell death inhibitor Bcl-2 overexpression, or p53-/- backgrounds, completely restored survival and development of Brca1-/- thymocytes; peripheral T cell numbers were not totally restored in Brcal-/- p53-/- mice; and that a mutant background for p21 (cyclin-dependent kinase inhibitor 1A) did not restore Brca1-/- thymocyte development, but partially restored peripheral T cell development. Thus, the outcome of Brca1 deficiency was dependent on cellular context, with the major defects being increased apoptosis in thymocytes, and defective proliferation in peripheral T cells.
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PMID:Brca1 required for T cell lineage development but not TCR loci rearrangement. 1088 Nov 67

Ras is essential for the transition from early B cell precursors to the pro-B stage, and is considered to be involved in the signal cascade mediated by pre-B cell antigen receptors. To examine the role of p21(ras) in the late stage of B cell differentiation, we established transgenic mice (TG) expressing a dominant-inhibitory mutant of Ha-ras (Asn-17 Ha-ras) in B lineage cells at high levels after the early B cell precursor stage. Expression of p21(Asn-17) (Ha-ras) was associated with a prominent reduction in the number of late pre-B cells, but had little effect on proliferation of early pre-B cells. Inhibition of p21(ras) activity markedly reduced the life span of pre-B cells, due, at least in part, to downregulation of the expression of an antiapoptotic protein, Bcl-xL. Thus, the apparent role for p21(ras) activity in pre-B cell survival may explain the decreased numbers of late pre-B cells in Asn-17 Ha-ras TG. Consistent with this possibility, overexpression of Bcl-2 in Asn-17 Ha-ras TG reversed the reduction in the number of late pre-B cells undergoing immunoglobulin light chain gene (IgL) rearrangement and progressing to immature B cells. These results suggest that p21(ras) mediates effector pathways responsible for pre-B cell survival, which is essential for progression to the late pre-B and immature B stages.
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PMID:Ras mediates effector pathways responsible for pre-B cell survival, which is essential for the developmental progression to the late pre-B cell stage. 1089 4

Apoptosis is a fundamental mechanism of cell death that can be engaged by a range of cellular insults. One of the major modes of action of chemotherapeutic drugs may be via the activation of apoptosis. Understanding how the cell death program is engaged following an insult, and hence why it fails to be engaged in certain settings, offers a novel approach to overcoming the clinical problem of drug resistance. The tumour suppressor gene p53 and its downstream effector genes p21, mdm-2, and gadd45 seem to be important in the cellular response to genotoxic drug induced damage. Considerable evidence has accrued about the effect of mutations of this pathway on drug sensitivity and this is discussed. The expanding Bcl-2 family of proteins also play an important role in the cell death program. Evidence suggests that these proteins may function as integrators of damage signals, and may be the final decision point as to whether a cell lives or dies. These proteins may thus represent a logical target for new approaches to overcoming drug resistance.
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PMID:Apoptosis and cancer chemotherapy. 1092 87

Although the aetiology of the hypopigmentary disorder vitiligo is ill understood, it is clear that pigment producing cells are absent from vitiliginous lesional skin. The present study was designed to investigate the possible role of melanocyte-expressed apoptosis regulatory molecules in melanocyte disappearance. Flow cytometric evaluation of p53, p21, Bcl-2 and Bax revealed no differences in in vitro expression levels between normal control and non-lesional melanocytes. Moreover, no in situ immunohistological differences were observed in melanocytes present in control, non-lesional and perilesional skin. However, an enhanced number of p53+ nuclei, in the absence of detectable p21 expression, was detected in involved areas. The observed p53 expression pattern did not involve melanocytes and could be the result of ultraviolet (UV) A irradiation. Further, we showed that UVB is capable of modulating melanocyte-expressed apoptosis regulatory molecules. Consequently, a lethal dose of UVB was given to two groups of cultured normal control and non-lesional melanocytes. No significant differences were found when comparing the percentages and kinetics of UVB-induced apoptosis in these groups. In conclusion, our results indicate that the relative apoptosis susceptibility of melanocytes in vitiligo is comparable with that of normal control cells. It is therefore unlikely that vitiligo is causally related to dysregulation of apoptosis regulatory molecules.
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PMID:Expression and modulation of apoptosis regulatory molecules in human melanocytes: significance in vitiligo. 1097 31

Bone morphogenetic proteins (BMPs), members of the transforming growth factor (TGF)-beta superfamily, are a group of related proteins that are capable of inducing the formation of cartilage and bone but are now regarded as multifunctional cytokines. We show in this report a novel function of BMPs in hematopoietic cells: BMP-2 induces apoptosis not only in human myeloma cell lines (U266, RPMI 8226, HS-Sultan, IM-9, OPM-2, and KMS-12 cells), but also in primary samples from patients with multiple myeloma. The mechanism of BMP-2-induced apoptosis was investigated with the use of U266 cells, which are dependent on the interleukin-6 autocrine loop. We showed that BMP-2 caused cell-cycle arrest in the G1 phase and the subsequent apoptosis of myeloma cells. BMP-2 up-regulated the expression of cyclin-dependent kinase inhibitors (p21(CIP1/WAF1) and p27(KIP1)) and caused hypophosphorylation of retinoblastoma (Rb) protein. In studies of apoptosis-associated proteins, BMP-2 was seen to down-regulate the expression of Bcl-x(L); however, BMP-2 had no effects on the expression of Bcl-2, Bax, or Bad. Therefore, BMP-2 induces apoptosis in various human myeloma cells by means of the down-regulation of Bcl-x(L) and by cell-cycle arrest through the up-regulation of p21(CIP1/WAF1) and p27(KIP1) and by the hypophosphorylation of Rb. Further analysis showed that the signal transducer and activator of transcription 3 (STAT3) was inactivated immediately after BMP-2 treatment. We conclude that BMP-2 would be useful as a novel therapeutic agent in the treatment of multiple myeloma both by means of its antitumor effect of inducing apoptotis and through its original bone-inducing activity, because bone lesions are frequently seen in myeloma patients.
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PMID:Bone morphogenetic protein-2 induces apoptosis in human myeloma cells with modulation of STAT3. 1097 40


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