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PubMed2006

Topotecan and methotrexate alter expression of the apoptosis-related genes BCL2, FAS and BCL2L12 in leukemic HL-60 cells.

The BCL2 family of genes (B-cell CLL/lymphoma 2; Bcl-2) plays a pivotal role in the highly regulated process of apoptosis. We have recently cloned a newly identified member of this family, BCL2L12, which was found to be differentially expressed in many tumors. It is known that topotecan and methotrexate act through induction of apoptosis in cancer cells. In the present study we investigated the expression profile of the novel apoptotic gene BCL2L12 in relation to other apoptotic genes in the human leukemic cell line HL-60, after treatment with topotecan or methotrexate. The kinetics of apoptosis induction and cell toxicity were investigated by DNA laddering and the MTT method, respectively. Gene expression levels were analyzed by RT-PCR using gene-specific primers. Downregulation of BCL2L12, BCL2 and FAS was observed after treatment of HL-60 cells with topotecan, while treatment with methotrexate led to downregulation of BCL2 and FAS, with no change in BCL2L12 expression. Our results support the significance of mRNA modulations in the expression of apoptosis-related genes during treatment of human leukemic cells with anticancer drugs.

Gene Expression Regulation, Neoplastic↗

PubMed2003

Bcl2-independent chromatin cleavage is a very early event during induction of apoptosis in mouse thymocytes after treatment with either dexamethasone or ionizing radiation.

We have quantified the emergence of early chromatin breaks during the signal transduction phase of apoptosis in mouse thymocytes after treatment with either ionizing radiation or dexamethasone. Dexamethasone at 1 microM can induce significant levels of DNA breaks (equivalent to the amount induced directly by 7.5 Gy ionizing radiation) within 0.5 h of treatment. The execution phase of apoptosis was not observed until 4-6 h after the same treatment. The presence of the Bcl2 transgene under the control of the p56lck promoter almost completely inhibited apoptosis up to 24 h after treatment, but it had virtually no effect on the early chromatin cleavage occurring in the first 6 h. Ionizing radiation induced chromatin cleavage both directly by damaging DNA and indirectly with kinetics similar to the induction of chromatin cleavage by dexamethasone. The presence of the Bcl2 transgene had no effect on the direct or indirect radiation-induced cleavage in the first 6 h, but after the first 6 h, the Bcl2 gene inhibited further radiation-induced chromatin cleavage. These results suggest that endonucleases are activated within minutes of treatment with either dexamethasone or ionizing radiation as part of the very early signal transduction phase of apoptosis, and prior to the irreversible commitment to cell death.

Animals↗

PubMedDate not supplied

Immunocytochemical and immunoelectron microscopical analysis of BCL2 expression in thyroid oxyphilic tumors.

In both human lymphoma and carcinoma, BCL2 expression contributes to the neoplastic development by preventing normal turnover due to programmed cell death. In thyroid carcinoma it was shown that BCL2 expression is related to cell differentiation and appears to be associated with a less aggressive behavior. Using immunogold electron microscopy labeling techniques on ultrathin frozen sections, the authors undertook an analysis of bcl-2 protein localization in 7 cases of thyroid tumor with (4 cases) or without (3 cases) oncocytic differentiation, which displayed histopathological features, corresponding to different degree of aggressiveness. All thyroid tumors and a lymphoblastoid cell line overexpressing BCL2 showed a preferential labeling of mitochondrial circumference, while the 4 cases with oncocytic differentiation displayed a bcl-2 protein location, not only on the circumference but also on the cristae of a consistent number of mitochondria. These results may indicate a bcl-2 protein interaction with intramitochondrial constituents related to the neoplastic transformation in oncocytic tumor.

Adenoma, Oxyphilic↗

PubMed2000

Clinical significance of the t(14;18) and BCL2 overexpression in follicular large cell lymphoma.

Follicular large cell lymphoma (FLCL) is an aggressive disease that responds to anthracycline-containing chemotherapy much like diffuse large B-cell lymphoma (DLBCL). Since the t(14;18) and/or bcl2 protein expression are less common in FLCL than in its low-grade counterparts, we sought to determine whether these features were predictive of survival as in DLBCL. We studied 50 patients with FLCL who were treated with curative intent. The t(14;18) was found by cytogenetic analysis in 56% of the patients and bcl2 protein was expressed by the tumor cells in 73%, but neither was predictive of survival. However, abnormalities of chromosome 17p and the presence of trisomy 21 were adverse predictors of survival, as were a number of clinical features. We conclude that neither the absence of the t(14;18) nor the lack of bcl2 expression explain the good response of a subset of patients with FLCL to curative therapy.

Aged↗

PubMed2001

Apoptosis, bcl2 expression, and cell cycle analyses in nickel(II)-treated normal rat kidney cells.

Nickel compounds are carcinogenic to human and are potent inducers of kidney and lung tumors in experimental animals. In this study, the effects of nickel(II) acetate on apoptosis, cell cycle and bcl2 expression in normal rat kidney (NRK- 52E) cells were investigated. Nickel(II) induced apoptosis in NRK-52E cells as demonstrated by DNA laddering. Apparent DNA laddering was observed in cells treated with 480 microM for 48 hr. In the flow cytometric analysis using propidium iodide fluorescence, an increase of cell proportion in G2/M phase was shown in cells exposed to at least 320 microM of nickel(II) acetate, from 7.7% for 0 microM of nickel(II) to 16.5% for 480 microM of nickel(II) acetate. Induction of apoptotic cell death by nickel(II) was accompanied by reduction of bcl2 protein expression, while the level of p53 protein was not changed. Taken together, our data indicate that nickel(II)-induced apoptosis in NRK-52E cells is accompanied by G2/M cell cycle arrest, regardless of p53 function, and that bcl2-mediated signaling pathway may be involved in positive regulation of nickel(II)-induced apoptotic cell death in NRK-52E cells.

Acetates↗

PubMed1999

Potent antitumor agent proteasome inhibitors: a novel trigger for Bcl2 phosphorylation to induce apoptosis.

The sustained cytotoxicity conferred by proteasome inhibitors against a broad spectrum of human cancer cells is mediated by a delicate mechanism of programmed cell death. Similar to microtubule disarraying agents, the cell death induced by these potent antitumor agents precedes blocking in cell cycle transition at G2-M phase. The microtubule damaging antineoplastic drugs can kill tumor cells by inducing phosphorylation of antiapoptotic proteins such as Bcl2, Bcl-xL or MCL-1. The simultaneous apoptosis with Bcl2 phosphorylation was evident in cancer cells challenged with the proteasome inhibitor, MG132. Our studies suggest that the proteasome inhibitor MG132 induced tumor cell killing is mediated through Bcl2 phosphorylation.

Antineoplastic Agents↗

PubMed1999

Inhibition of the MAPK pathway abrogates BCL2-mediated survival of leukemia cells after exposure to low-dose ionizing radiation.

The ability of low-dose ionizing radiation (1 Gy) to modulate the activities of the mitogen-activated protein kinase (MAPK) and Jun NH2-terminal kinase (JNK1) cascades in human myeloid leukemia (HL60/pCEP4) cells and in cells overexpressing the anti-apoptosis protein BCL2 (HL60/Bcl-2) was investigated. Radiation exposure caused prolonged (3-4 h) activation of MAPK in HL60 cells. The ability of radiation to activate the MAPK pathway was attenuated by 30% in cells overexpressing BCL2. In contrast, low-dose irradiation of HL60/pCEP4 and HL60/Bcl-2 cells failed to modulate JNK1 activity. Inhibition of the MAPK pathway by use of the specific MEK1/2 inhibitor (10 microM PD98059) in both HL60/pCEP4 and HL60/Bcl-2 cells prior to irradiation permitted a similar prolonged radiation-induced activation of JNK1. Furthermore, combined treatment with PD98059 and radiation in both cell types caused a large decrease in growth of cells in suspension culture, a large increase in apoptosis, and a 90% decline in clonogenicity when compared to either treatment alone. Reduced proliferation after combined irradiation and PD98059 treatment in both cell types correlated with reduced Cdc2 activity and arrest in G2/M phase of the cell cycle. These data demonstrate that inhibition of MEK1/2 leading to blockade of the MAPK activation increases the radiation sensitivity of HL60 cells and decreases the ability of these cells to recover from the radiation-induced arrest at the G2/M-phase cell cycle checkpoint. In addition, our data demonstrate that elevated expression of BCL2 does not abrogate the ability of inhibition of MAPK to potentiate radiation-induced cell death in HL60 cells.

Apoptosis↗

PubMed1992

Analysis of BCL2 and MYC expression in non-Hodgkin's lymphomas by in situ hybridization: correlation with chromosome translocations.

We have used an in situ hybridization method for analysis of expression of BCL2 and MYC on cytospun preparations of normal and malignant lymphoid cell lines and tissue sections of normal and malignant lymph nodes. The probes comprised 50-mer antisense oligonucleotides starting at the ATG codons of exon 3 of BCL2 and exon 2 of MYC. We studied the expression of these two genes in frozen tissue sections of biopsy specimens derived from normal and hyperplastic lymph nodes, B-cell lymphomas carrying the t(14;18)(q32;q21) and t(8;14)(q24;q32) translocations, and T-cell lymphomas with clonal chromosome abnormalities. While all proliferating cells expressed both genes, BCL2 expression was increased two- to threefold in follicular lymphomas with t(14;18) and MYC expression was increased two- to four-fold in high-grade lymphomas with t(8;14). These results are consistent with previous data on deregulated expression of these genes obtained from study of lymphoma cell lines carrying the relevant translocations.

Base Sequence↗

PubMed2005

An immunohistochemical comparison between low-grade and high-grade ovarian serous carcinomas: significantly higher expression of p53, MIB1, BCL2, HER-2/neu, and C-KIT in high-grade neoplasms.

Ovarian serous carcinoma (OSC) is the most common ovarian epithelial malignancy. Recently, a dualistic pathway of ovarian serous carcinogenesis has been proposed based on morphologic observations and molecular genetic analysis. In this scheme, low-grade OSC arises in a stepwise fashion from a benign serous cystadenoma through a usual serous borderline tumor through a micropapillary variant of serous borderline tumor. In contrast, the more common high-grade OSC arises de novo from the ovarian surface epithelium or the epithelium of cortical inclusion cysts with an as yet unrecognized precursor lesion. Although the division of OSC into low- and high-grade variants is gaining greater acceptance, and although there is accumulating molecular genetic evidence for this, there is little published information regarding a comparison of protein expression between these two types of OSC. In this study, we have investigated the immunohistochemical expression of a wide range of proteins in cases of low-grade (n = 22) and high-grade (n = 47) OSC. Antibodies used were p53, MIB1, BCL2, WT1, HER-2/neu, C-KIT, osteopontin, and survivin. For all antibodies, except MIB1, cases were scored as 0 (negative or occasional positive cells), 1+ (<10% cells positive), 2+ (10%-25% cells positive), 3+ (26%-50% cells positive), 4+ (51%-75% cells positive) or 5+ (>75% cells positive). For MIB1, the percentage of positive nuclei was calculated. There was a statistically significant higher expression of p53, MIB1, BCL2, HER-2/neu, and C-KIT in high-grade compared with low-grade OSC (P < 0.05). Thirty of 47 (64%) cases of high-grade OSC exhibited 5+ staining with p53 compared with 4 of 22 (18%) low-grade neoplasms. Twelve of 47 (26%) high-grade OSCs exhibited 5+ staining with BCL2 compared with 1 of 22 (5%) low-grade OSCs. The mean MIB1 proliferative index in high-grade OSCs was 55.4% compared with 23.0% in low-grade OSCs. Virtually all cases of both low-grade and high-grade OSCs exhibited diffuse nuclear positivity with WT1 and diffuse cytoplasmic positivity with survivin. Osteopontin expression was variable with no significant difference in expression between low-grade and high-grade OSC. Although expression of both HER-2/neu and C-KIT was significantly higher in high-grade compared with low-grade OSC, only rare cases exhibited strong positivity with these antibodies, which could be of therapeutic value in individual cases, although this would require additional molecular investigations. The significant differences in protein expression between low-grade and high-grade OSC provides further support for a different underlying pathogenesis. In particular, the differences in p53 immunoreactivity are in keeping with the observation that p53 gene mutation is more common in high-grade than low-grade OSC.

Biomarkers, Tumor↗

PubMed2005

Abnormalities of the P53, MDM2, BCL2 and BAX genes in acute leukemias.

Abnormalities of the P53 network have been implicated in the pathogenesis of acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML). The purpose of this study was to define P53 gene mutations, to detect MDM2 gene amplification and to estimate mRNA expression of P53, MDM2, BCL2 and BAX genes in patients with ALL and AML. Twenty-five patients with ALL and 65 patients with AML, both recently diagnosed, were included into this study. Exons 5-8 of the P53 gene with flanking intronic sequence were amplified by the polymerase chain reaction (PCR) method and subjected to mutation screening by single-strand conformation polymorphism analysis (SSCP). Mutation of the P53 gene was found in one patient of the 25 with ALL and in five patients of the 65 with AML. Sequence analysis was subsequently performed. One mutation in intronic sequence in ALL and four missense mutations and one silent nucleotide substitution in AML were identified. Amplification of MDM2 gene was detected by multiplex-PCR analysis in only one sample from patient with ALL, but was not observed in any case of AML. To gain further insight into the role of P53 network in the evolution of acute leukemias, the P53, MDM2, BCL2 and BAX mRNAexpressions in portion samples from patients with ALL and AML were analyzed using multiplex RT-PCR. Although a low frequency of molecular disturbances of the P53 and the MDM2 genes was detected in this study, there was a high percentage of cases with increased mRNA level of P53 and MDM2. A high frequency of BCL2 mRNA overexpression and a relatively low frequency of BAX mRNA overexpression detected in both analyzed leukemias in this study, indicate that altered transcription of these genes may be involved in leukemogenesis.

Adolescent↗

PubMed1994

Detection of BCL2 rearrangement in archival cytological smears of B-cell lymphomas.

The application of polymerase chain reaction (PCR) to cytological material represents a promising, relatively noninvasive approach to clinical molecular genetic analysis. The detection rate of the t(14;18), the most common translocation in B-cell lymphomas, which results in rearrangement of the immunoglobulin heavy chain (IGH) and BCL2 genes, has not been examined in archival cytological smears. We studied 10 cases of lymphoma that showed a cytogenetic t(14;18) in a surgical specimen and for which were available both lymphoma DNA from the same specimen and prior or subsequent archival cytological smears, either FNA or exfoliative, diagnosed as positive for lymphoma. The paired DNA samples, respectively extracted from the archival smears and frozen surgical biopsy tissue, representing clinical intervals of up to 20 mo, were studied in each case by PCR with IGH and BCL2 major breakpoint region primers. In four cases, the same clonotypical PCR product was seen in both samples. In four other cases, neither sample yielded a PCR product--these cases were also negative by Southern blotting using a BCL2 major breakpoint region probe. In one case, the PCR product could only be demonstrated in DNA from frozen tissue. Finally, in one other case, a PCR product was only detected in DNA from archival cytological smears. Thus, the overall concordance of PCR results in the paired DNA samples was 80%. Our findings suggest that, in cases of B-cell lymphoma previously characterized by PCR, the t(14;18) can be detected in archival cytological smears in the majority of cases, thereby providing valuable data regarding the clonal derivation of metachronous lymphoma samples in which only cytological material is obtained.

Adult↗

PubMed1998

p53 mutant immunophenotype and deregulation of p53 transcription pathway (Bcl2, Bax, and Waf1) in precursor bronchial lesions of lung cancer.

Lung cancer is the end result of a multistep process in which genetic and molecular changes accompany, in an unknown temporal sequence, histological precursor (preinvasive) bronchial lesions. Biomarkers allowing prediction of the rate of progression of precursor lesions at different locations in the anatomical field may be clinically useful. Toward this aim, we analyzed, using immunohistochemistry, the expression of the p53 gene and of its transcriptional target genes bax, bcl2, and waf1 in preinvasive bronchial lesions from 69 patients with lung cancer and in similar lesions from 20 patients with no cancer progression. p53 accumulation occurred with increasing frequency, from 19% in mild dysplasia to 36% in moderate dysplasia and 59% in carcinoma in situ, and was exclusively observed in patients with p53-positive carcinoma. The higher frequency of the p53-positive immunophenotype in lesions adjacent to the p53-positive carcinoma, as compared to lesions distant from it, suggests that p53 mutant preneoplastic lesions had a higher rate of progression to invasion than did p53-negative lesions. Similar lesions in patients with no progression to lung cancer were all p53 negative. Bcl2 overexpression and Bax down-regulation, as shown by immunostaining, occurred in preinvasive lesions and were mainly maintained during invasion. The expressions of bax, bcl2, and waf1 did not correlate with p53 status. We conclude that p53 stabilization in preinvasive lesions has high predictive value for progression to invasion and that Bax/Bcl2 imbalance contributes to the clonal expansion during premalignant states.

Bronchial Neoplasms↗

PubMed1996

Prostatic cell lineage markers: emergence of BCL2+ cells of human prostate cancer xenograft LuCaP 23 following castration.

A model of prostate cancer progression based on the expression pattern of informative genes in the human prostate cancer xenograft LuCaP 23.1 is presented. Apparently, there are at least 2 tumor cell populations of LuCaP 23.1, representing 2 different phenotypes. One is NSE (neuron-specific enolase)-positive and the other NSE-negative. NSE-positive tumors were recovered after hormone-independent growth in castrated mice. These hormone-independent tumors also expressed BCL2, a gene product shown to inhibit apoptosis. With NSE, BCL2 and PSA (prostate-specific antigen) as identifying markers, the model specifies a putative progression sequence of the prostate cancer cell types. We also show a proposed lineage relationship among the 3 principal normal cell types found in the prostatic epithelium.

Animals↗

PubMed2006

p53 apoptotic response to DNA damage dependent on bcl2 but not bax in head and neck squamous cell carcinoma lines.

BACKGROUND: In many tumors, the p53 gene has been mutated or deleted. p53 null mutant mice are prone to development of a variety of neoplasms at an early age. In head and neck cancer, p53 mutations are detected in most cases. p53 has been shown to induce growth arrest, differentiation, and death when overexpressed in cancer cell lines. p53 responds to DNA damage by arresting the cell cycle in G1 or G2 phase until repair can be completed. If DNA damage is severe, p53 may trigger programmed cell death by means of proapoptotic genes such as bax. Studies have suggested that p53 target genes must be intact for proper functioning of the tumor suppressor. METHODS: We stably expressed transcriptionally active p53 in head and neck squamous cell carcinoma (SCC) lines in which the endogenous gene was inactivated by mutation. We performed proliferation, cell death, cell cycle, and gene expression analysis in control clones and those treated with the DNA damaging agent etoposide. RESULTS: These clones proliferated slowly with accumulation of cells at the G1/S phase boundary but did not undergo growth arrest or apoptosis. Coexpression of the proapoptotic gene bax (a known target of p53) failed to induce apoptosis in these clones. However, p53 expression sensitized these cells to DNA damage-induced apoptosis by means of inhibition of bcl2 protein levels. CONCLUSION: We concluded that the p53 apoptotic response to DNA damage was dependent on bcl2 but not bax in head and neck SCC lines.

Apoptosis↗

PubMed2005

Lack of Bcl-2 expression in follicular lymphoma may be caused by mutations in the BCL2 gene or by absence of the t(14;18) translocation.

Follicular lymphoma (FL), except grade 3B, is characterized by the chromosomal translocation t(14;18)(q32;q21), which results in over-expression of the Bcl-2 protein. Ten per-cent of all FLs, however, do not show Bcl-2 protein expression with standard immunohistochemistry using a monoclonal Bcl-2 antibody against residues 41-54 of the Bcl-2 protein. In this study, the biological background of 18 Bcl-2-negative FL cases grade I, II, or IIIa was investigated by immunohistochemical staining and western blot analysis with alternative antibodies. Bcl-2 protein was demonstrated in five of the 18 cases and all of these carried the t(14;18) translocation. Of the 13 cases that were Bcl-2 negative with alternative antibodies, 12 lacked the t(14;18) translocation. PCR and subsequent sequence analysis of cDNA demonstrated that three cases with a t(14;18) contained somatic mutations in the translocated BCL2 gene, resulting in amino acid replacements in the region of the epitope recognized by the antibody. In conclusion, the majority of Bcl-2-negative FL lack a t(14;18) but a significant subset of these tumours are false negative due to mutations in the BCL2 gene. These findings may have consequences for the use of Bcl-2 immunohistochemistry for diagnostic purposes.

Biomarkers, Tumor↗

PubMed1997

Complex interplay among apoptosis factors: RB, p53, E2F, TGF-beta, cell cycle inhibitors and the bcl2 gene family.

Apoptosis is a fundamental cell program as important as growth, differentiation and quiescence. It regulates tissue development, homeostasis and it is a basic defence against cancer. The cell can undertake multiple apoptotic pathways, where different elements are involved. In this report, we would like to stress particularly that the p53/RB pathway and its complex, interplay with the bcl2 gene family, where paramount elements of apoptosis regulation are operating. It is generally believed that bcl2 blocks apoptosis at the level of the activation of ICE-(Interleukin Converting Enzymes)-like proteases [1,2]. The interconnection between apoptosis and cell cycle is very important and complex and we will start the story from this very up-to-date point of view.

Animals↗

PubMed1992

Detection of canine homologs of human MYC, BCL2, IGH, and TCRB genes by Southern blot analysis.

Subsets of non-Hodgkin's lymphoma in humans have been shown to involve activation of protooncogenes such as MYC and BCL2 resulting from chromosome translocation involving the IGH and TCR genes. Malignant lymphomas in the canine present histologic and clinical subsets similar to those in humans. To study the genetic nature of these lymphomas, we undertook this study to determine, by Southern blotting analysis, the extent of homology between the human and canine genes MYC, BCL2, IGH, and TCRB using human gene probes. Our results, presented here, show that the organization of these genes in the two species is very similar.

Animals↗

PubMed1993

Lack of 5' BCL2 rearrangements in B-cell leukemia.

We found no rearrangements in the 5' region of the BCL2 gene in DNA samples from 60 patients with chronic B-cell leukemia (CLL). This compares with the presence of these rearrangements in up to 10% of patients in other reports, and suggests that the incidence of 5' BCL2 rearrangements in CLL is considerably less than 10%.

DNA, Neoplasm↗