Programmed cell death by bcl-2-dependent and independent mechanisms in B lymphoma cells.

Cuende, Eduardo; Alés-Martínez, JoséE.; Ding, Liang; González-Garcı́a, Maribel; Martı́nez, Carmen; Núñez, Gabriel

doi:10.1002/j.1460-2075.1993.tb05799.x

Cited by 132 publications

(66 citation statements)

References 48 publications

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“…44 The coexistence of high percentages of bcl-2 + cells and increased AI could tentatively be explained by bcl-2 independent pathways to programmed cell death. 45 In conclusion, our data suggests the existence of subsets of DCIS and IDC that, because of their phenotypic characteristics, could be derived from subpopulations of normal breast cells, which probably use different control mechanisms of cell proliferation and neoplastic progression-p53 dependent in the cases with a stem cell phenotype and p53 independent in the cases with a luminal cell phenotype. In fact, the liability of a given tumour to exhibit p53 mutation seems to be predetermined by the nature of its cell of origin, depending more specifically to what extent wild-type p53 forms a rate limiting step in the control of the proliferating life span in that cell.…”

Section: Discussionmentioning

confidence: 68%

p53 mutation in breast cancer. Correlation with cell kinetics and cell of origin

Megha

Ferrari²,

Benvenuto³

et al. 2002

Journal of Clinical Pathology

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Aim: Several studies have investigated the expression of the cytokeratins (CKs), vimentin, the epithelial growth factor receptor (EGFR), the oestrogen receptor (ER), and the progesterone receptor (PgR), in breast cancer, but no study has directly compared p53 mutations with these phenotypic and differentiation markers in the same case. The present study was designed to provide some of this information. Methods: The expression of the p53 and bcl-2 proteins was evaluated by immunohistochemistry in relation to phenotypic characteristics and cellular kinetic parameters (mitotic index and apoptotic index) in 37 cases of ductal carcinoma in situ (DCIS) and 27 cases of infiltrating ductal carcinoma (IDC) of the breast. In addition, p53 gene mutation was examined by polymerase chain reaction single strand conformation polymorphism analysis (SSCP). Results: Thirteen cases (eight DCIS and five IDC) showed expression of CK8, CK14, CK18, vimentin, and EGFR, consistent with a stem cell phenotype, whereas 44 cases (27 DCIS and 17 IDC) showed expression of CK8 and CK1, weak or negative expression of CK18, but were negative for vimentin and EGFR, consistent with a luminal cell phenotype. DCIS and IDC cases with a stem cell phenotype were ER/PgR negative and intermediately or poorly differentiated. In contrast, the cases with luminal cell phenotype were ER/PgR positive and well or intermediately differentiated. In addition, intermediately or poorly differentiated cases with a stem cell phenotype showed higher proliferative activity (per cent of MIB-l positive cells) than did intermediately or well differentiated cases with a luminal cell phenotype. Both DCIS and IDC cases with a stem cell phenotype were p53 positive and bcl-2 negative by immunohistochemistry. In IDC, p53 expression was associated with a reduction of both mitotic index and apoptotic index compared with DCIS. Most of the tumours showing a more differentiated phenotype (luminal) were p53 negative and bcl-2 positive. In these cases, cell kinetic parameters increased from DCIS to IDC. These data suggest the existence of subsets of DCIS and IDC that, because of their phenotypic characteristics, could be derived from subpopulations of normal breast cells having different control mechanisms of cell proliferation and neoplastic progression. Conclusions: These results are compatible with the hypothesis that the phenotype of the cell of origin constrains both tumour phenotype and the choice of genetic events; however, the occurrence of p53 mutants by chance during neoplastic transformation cannot be excluded.

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Section: Discussionmentioning

confidence: 68%

p53 mutation in breast cancer. Correlation with cell kinetics and cell of origin

Megha

Ferrari²,

Benvenuto³

et al. 2002

Journal of Clinical Pathology

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“…The description of the expression vectors for wt (pC53-SN3) and mutant p53: 143 V?A (pC53-SCX3) (Kern et al, 1992); mutant p53: 249 R?S (pC53-249) (Ponchel et al, 1994); c-Ha-ras (pEJ-ras) and c-myc (Land et al, 1983); SV40-TAg (pCMV-T) (Dimri et al, 1996); human Bcl-2 (bcl2-pSFFV-neo) (Cuende et al, 1993), baculovirus p35 (p35-pSFFV-neo) (Qi et al, 1997); adenovirus E1B (pCMVE1B) (White et al, 1991), and cowpox protein crmA (pHD1.2 crmA) (Susin et al, 1997) has been published. We thank H Schaller (pMX and mutants), B Vogelstein (wt p53 and mutant 143), M O È ztuÈ rk (mutant p53-249), B Luber (cHa-ras and c-myc), J Campisi (SV40TAg), CW Distelhorst (p35 and Bcl-2), E White (E1B) and MA Buendia (crmA) for providing the indicated constructs.…”

Section: Pcdna-p21 Rat P21mentioning

confidence: 99%

Induction of apoptosis by the transactivating domains of the hepatitis B virus X gene leads to suppression of oncogenic transformation of primary rat embryo fibroblasts

2000

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Epidemiology shows a clear correlation between chronic infection with the hepatitis B virus (HBV) and development of hepatocellular carcinoma (HCC). The potential role of the transactivating hepatitis B virus X protein (HBx) in transformation by HBV is controversial. Here we report that HBx suppresses transformation of primary rat embryo ®broblasts (REFs). Cooperating oncogenes like c-Ha-ras and c-myc transform REF very eciently but cotransfection with HBx suppressed transformation of REFs down to 5%. Similarly, transfection of HBx together with the cooperating oncogenes Ha-ras and SV40 LTAg or c-Ha-ras and mutant p53 reduced the number of foci to 13%. Comparable results were obtained with HBx in the context of the whole HBV. Suppression of focus formation in REF could be partly relieved by cotransfection of apoptosis inhibitors Bcl-2 or E1B. However, cotransfection of apoptosis inhibitors crmA and p35 did not in¯uence the proapoptotic functions of HBx. Thus, HBx may speci®cally activate the Bcl-2 sensitive pathway leading to apoptosis. Experiments with 13 HBx linker scanning mutants revealed that the domains necessary for HBx dependent transactivation overlap with the domains needed for the apoptotic/growth arrest functions of HBx.

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“…MDA-MB-468 cells were transfected by the calcium phosphate method (GIBCO/BRL Calcium Phosphate Transfection System) with the pSFFV-Bcl-2 expression vector, described previously (Cuende et al, 1993). Stable transfectants were isolated by resistance to G418.…”

Section: Vector Construction and Transfectionmentioning

confidence: 99%

Baculovirus p35 and Z-VAD-fmk inhibit thapsigargin-induced apoptosis of breast cancer cells

Zhong

et al. 1997

Oncogene

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Programmed cell death, or apoptosis, is inhibited by the antiapoptotic oncogene, Bcl-2, and is mediated by a cascade of aspartate-speci®c cysteine proteases, or caspases, related to interleukin 1-b converting enzyme. Depending on cell type, apoptosis can be induced by treatment with thapsigargin (TG); a selective inhibitor of the endoplasmic reticulum-associated calcium-ATPase. The role of caspases in mediating TG-induced apoptosis was investigated in the Bcl-2-negative human breast cancer cell line, MDA-MB-468. Apoptosis developed in MDA-MB-468 cells over a period of 24 ± 72 h following treatment with 100 nM TG, and was prevented by Bcl-2 overexpression. TG-induced apoptosis was associated with activation of caspase-3 and was inhibited by stable expression of the baculovirus p35 protein, an inhibitor of caspase activity. Also, TG-induced apoptosis was inhibited by treating cells with Z-VAD-fmk, a cellpermeable¯uoromethylketone inhibitor of caspases. These ®ndings indicate that TG-induced apoptosis of MDA-MB-468 breast cancer cells is subject to inhibition by Bcl-2 and is mediated by caspase activity. This model system should be useful for further investigation directed toward understanding the role of calcium in signaling apoptosis, and its relationship to Bcl-2 and the caspase proteolytic cascade.

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Programmed cell death by bcl-2-dependent and independent mechanisms in B lymphoma cells.

Cited by 132 publications

References 48 publications

p53 mutation in breast cancer. Correlation with cell kinetics and cell of origin

p53 mutation in breast cancer. Correlation with cell kinetics and cell of origin

Induction of apoptosis by the transactivating domains of the hepatitis B virus X gene leads to suppression of oncogenic transformation of primary rat embryo fibroblasts

Baculovirus p35 and Z-VAD-fmk inhibit thapsigargin-induced apoptosis of breast cancer cells

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