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PubMed2000

BAX and PKCalpha modulate the prognostic impact of BCL2 expression in acute myelogenous leukemia.

Previously, we demonstrated that the level of BCL2 expression is prognostic in acute myelogenous leukemia (AML). High levels of BCL2 correlate with an adverse outcome when associated with favorable and intermediate prognosis cytogenetics (FIPC), whereas low levels portend an adverse outcome when associated with unfavorable cytogenetics (UC). Because BCL2 function can be modulated by dimerization with family members, like BAX, or by phosphorylation by protein kinase C alpha (PKCalpha), we hypothesize that the relative expression of these proteins in primary leukemic cells might alter the prognostic impact of BCL2 expression. We therefore measured BAX and PKCalpha protein levels in peripheral blood mononuclear cell lysates from 165 newly diagnosed AML patients and correlated the expression of these proteins with BCL2 expression, patient survival, and remission induction success. Expression levels of BAX and PKCalpha were normalized against a control cell line, K562. BAX and PKCalpha expression levels were heterogeneous and did not correlate with the percentage of blasts in the sample (R2 = 0.01 and <0.01). The median expression of both was similar across FAB groups but the range was greater for M4. A similar distribution of expression was observed in all cytogenetic groups, except that patients with inversion 16 demonstrated lower levels of BAX. Individually, neither PKCalpha nor BAX expression was prognostic of response to induction therapy or survival. A similar outcome was obtained when patients were stratified by cytogenetics into FIPC and UC groups. However, the ratio of either BCL2:BAX (B2:BX) or PKCalpha*B2:BX (PK*B2:BX) was highly prognostic. Patients with FIPC and a lower ratio (less than median) of either B2:BX or PK*B2:BX had a significantly higher remission induction rate (88 versus 69%, P = 0.04) and longer survival (median: 141 versus 80.5 weeks, P = 0.007) compared with those with ratios more than median. For patients with UC, values of either B2:BX or PK*B2:BX below the median had an inferior response rate to induction therapy (35 versus 78%, P = 0.0006) and inferior survival outcomes (median survival: 11 versus 53 weeks, P = 0.00002). Interestingly, FIPC and UC patients with antiapoptotic ratios (defined as B2:BX or PK*B2:BX more than median) had identical response rates and survival outcomes. In multivariate analyses, the compound variables of cytogenetics and B2:BX, or PK*B2:BX were independent predictors of survival. These results suggest that expression levels of proteins that affect the functional status of BCL2 modify the prognostic impact of BCL2 and suggest that the role of apoptosis in different cases of AML varies independently in the different cytogenetic subgroups.

Adolescent↗

PubMed2000

V(D)J recombinase-mediated transposition of the BCL2 gene to the IGH locus in follicular lymphoma.

Using DNA fiber fluorescence in-situ hybridization (FISH) and 3-color interphase FISH, 2 cases of follicular lymphoma were identified in which the BCL2 gene was excised from 18q21 and inserted into the immunoglobulin heavy chain (IGH) locus at 14q32. Both the insertion breakpoint at 14q32 and the deletion breakpoint at 18q21 were cloned using inverse polymerase chain reaction. Sequence analysis showed that the JH sequences were juxtaposed to the 5'-side of BCL2, and the DH sequences were juxtaposed to the 3'-side of BCL2. There were breakpoints at both the JH and DH recombination signal sequences, and N-nucleotides were present at all breakpoint junctions. At the BCL2 locus, the 3'-breakpoints in both cases were localized at exactly the same nucleotide position, 6. 2 kilobase downstream of the major breakpoint region, directly adjacent to a complete cryptic recombination signal sequence (RSS) consisting of a heptamer, a nonamer, and a 23-base pair (bp) spacer. The BCL2 5'-breakpoints were approximately 600 bp upstream of the gene, within the CA repeats. Although less evident than for the BCL2 3'-breakpoints, cryptic RSSs were also identified at these breakpoints, with a 12-bp spacer. On the basis of structural characteristics of these rearrangements, a model is proposed in which the BCL2 gene is deleted from its locus by recombination activation gene-1/-2 (RAG-1/-2)-mediated excision. The gene is subsequently inserted into the recombining IGH locus, a process involving the formation of hybrid joints between the IGH coding ends and the BCL2 signal ends. (Blood. 2000;96:1947-1952)

Base Sequence↗

PubMed2002

Signal-induced site specific phosphorylation targets Bcl2 to the proteasome pathway.

The oncogene derived protein Bcl2 and its family members such as Bcl-xL or Mcl-1 can confer negative control in the pathway of cellular suicide machinery. The reversible phosphorylation of the components in the apoptotic-signaling pathway is likely to be an important regulatory mechanism to control the fate of a cell. Previous reports by others and us demonstrate that phosphorylation of anti-apoptotic proteins such as Bcl2, Bcl-xL or Mcl-1 can regulate their function depending on the apoptotic trigger or cell type. Also, evidence is now accumulating that the ubiquitin proteasome pathway can play an important role in apoptosis. In order to understand whether any cross-talk exists between proteasome and Bcl2 phosphorylation pathways, studies were undertaken employing cell permeable proteasome inhibitors. When proteasomes were inactivated, enhanced accumulation of slower mobility forms of Bcl2 was clearly evident. Due to substitution of the major phosphorylation sites Ser 70, 87 to Ala, no such effect was observed. It is known that in contrary to phospho Bcl2, native Bcl2 (non-phosphoform) is unable to associate with cis-trans peptidyl prolyl isomerase Pin1-a key factor to regulate the fate of phosphoforms of Bcl2 and apoptosis. Thus the enhanced resistance to cell death exhibited by phosphorylation defective mutant Bcl2 might be attributed to its inability to associate with Pin1.

Alanine↗

PubMed1996

Concurrent activation of MYC and BCL2 in B cell non-Hodgkin lymphoma cell lines by translocation of both oncogenes to the same immunoglobulin heavy chain locus.

Concurrent activation of BCL2 and MYC usually occurs in B cell non-Hodgkin lymphoma (B-NHL) by translocation of both oncogenes to both immunoglobulin heavy chain (IGH) alleles: this abrogates immunoglobulin synthesis. We have studied three B-NHL cell lines (DoHH2, VAL and ROS 50) and show that concurrent activation of BCL2 and MYC may follow translocation of both oncogenes to the same IGH allele. Conventional cytogenetics of DoHH2 suggested the presence of a t(14;18)(q32;q21) translocation. However, fluorescent in situ hybridization (FISH) studies using whole chromosome paints, alpha satellite probes and flow-sorted chromosomes as probes revealed an unexpected complexity of rearrangements involving chromosomes 8, 14 and 18, namely t(8;14;18)(q24;q32;q21). DNA blot and previous PCR analysis confirmed the juxtaposition of BCL2 major breakpoint region (mbr) with IGJH6, but also demonstrated a rearrangement within the first exon of MYC. The centromeric (5') MYC rearranged fragment comigrated with the BCL2-JH6 rearranged fragment in BamHI, EcoRI and Bg/II restriction digests. The der(8)t(8;14;18) therefore comprised 5' MYC (exon I)-Sgamma4-JH6-BCL2 mbr. Similar rearrangements were observed in both ROS 50 and VAL cell lines which contained two and three copies of the der(8)t(8;14;18) respectively. Quantitative flow cytometry for BCL2 and MYC expression showed abundant expression of both proteins in all three lines. These data indicate the der(14)t(14;18)(q32;q21) may itself be the target for any second translocation. The presence of the intact BCL2-JH fusion gene on the der(8)t(8;14;18) allowed concurrent activation of both BCL2 and MYC with no loss of immunoglobulin expression.

Aged↗

PubMed1999

CD40 and Bcl2 expression in squamous cell carcinoma of the lung: correlation with apoptosis, survival, and other clinicopathological factors.

CD40 is a cell surface receptor which, when ligated, modulates apoptosis in some cell types, perhaps via activation of the expression of members of the Bcl2 gene family. This study sought to determine whether expression of CD40 in a series of 134 squamous cell carcinomas (SCCs) of the lung was related to apoptosis or clinical parameters, either alone or in connection with Bcl2 expression. Sections of SCCs were stained for CD40 and Bcl2 by immunohistochemical techniques. An index was determined for these two markers by counting stained and unstained malignant cells under high power. Sections were also stained by haematoxylin and eosin for determination of the apoptotic index by counting apoptotic bodies. About 40 per cent of SCCs expressed CD40 in at least some of the malignant cells, with about 10 per cent essentially uniformly stained. Similar proportions expressed Bcl2, with a tendency for expression to be mutually excluisve. Apoptosis did not correlate with CD40 expression, nor was there evidence of a co-operative or an antagonistic effect with Bcl2. Bcl2 expression, on the other hand, correlated significantly with the apoptosis score. CD40 expression showed no significant relationship with survival or any other clinicopathological parameter except ploidy. Bcl2 expression, however, correlated with longer survival. It is concluded that CD40 expression in SCC of the lung does not by itself relate to apoptosis, nor is it a useful indicator of prognosis.

Adult↗

PubMed2004

Identification of variants in cyclin D1 ( CCND1) and B-Cell CLL/lymphoma 2 ( BCL2).

CCND1 is an important cell-cycle regulatory protein associated with cell proliferation, poor prognosis and recurrence in cancer, while BCL2 is an important anti-apoptotic protein that plays a vital role in the regulation of the life span by controlling the rate of apoptosis. Recent studies have shown that CCND1 and BCL2 may be responsible for the body mass and the regulation of various metabolic processes. In an effort to discover additional polymorphism(s), we scrutinized the genetic polymorphisms in the CCND1 and BCL2. By direct DNA sequencing in 24 individuals, we identified 22 sequence variants within the 16 kb of whole CCND1 gene: one in exon 4, 17 in introns and four in the 3' UTR region. We also found eight sequence variants within 7.5 kb exon-intron boundaries of BCL2 gene: one in promoter, three in exon 1, and four in the 3' UTR region. Haplotypes, their frequencies and linkage disequilibrium coefficients (| D'| and r(2)), among polymorphisms were estimated. Among identified variants, seven and six variants of CCND1 and BCL2 were genotyped in a larger series of subjects ( n=320). Statistical analyses of CCND1 and BCL2 polymorphisms with two metabolic phenotypes revealed no significant association. The information concerning genetic polymorphisms of CCND1 and BCL2 might provide valuable information for future genetic studies of diseases.

5' Untranslated Regions↗

PubMed1995

Class switch recombination of the immunoglobulin heavy chain gene frequently occurs in B-cell lymphomas associated with rearrangement of the BCL2 gene.

B-cell lymphomas, mainly follicular lymphomas, carrying a t(14;18) chromosomal translocation associated with rearrangement of the BCL2 gene and the immunoglobulin heavy chain (IGH) gene, share many similarities with germinal center B cells in the secondary lymphoid follicle. In the germinal center, antigen-stimulated B cells proliferate and differentiate while undergoing isotype class switching of their immunoglobulin heavy chains. To examine whether BCL2-positive lymphoma cells show class switch recombination similar to that in the germinal center B cells, we studied the genomic configurations of the IGH gene loci in 38 patients with B-cell lymphomas. Sixteen (80%) out of 20 patients with BCL2-positive lymphomas showed class switch recombination on translocated and/or productive IGH gene loci. Lymphoma cells from 7 of the 16 patients expressed the gamma-heavy chain on their surfaces, indicating functional class switching to the gamma-constant gene on the productive allele. By contrast, 6 (33%) of the 18 patients lacking the BCL2 rearrangements exhibited class switch recombination. Statistical analysis revealed that the BCL2-positive lymphomas underwent switch recombination on either allele at a significantly higher frequency than the BCL2-negative lymphomas (P = 0.0099). This indicates that follicular lymphoma, not only morphologically but also functionally, recapitulates the germinal center. We propose that the up-regulated BCL2 expression itself is capable of playing an important role in immunoglobulin class switching.

Gene Rearrangement↗

PubMed2006

Prognostic value of the apoptosis related genes BCL2 and BCL2L12 in breast cancer.

Many members of BCL2 (Bcl-2) apoptosis-related genes were found to be differentially expressed in various malignancies and were proposed as prognostic cancer biomarkers. Recently, a new member of the BCL2 gene family, BCL2L12, was cloned and was found to be expressed in mammary gland. In the present study, 55 specimens from patients with, histologically confirmed, epithelial breast carcinoma were analyzed for BCL2 and BCL2L12 gene expression by RT-PCR. Increased expression of BCL2 gene was found in patients belonging to the age groups <45 or >55 years, as well as in estrogen receptors (ER)-positive patients and in BCL2L12-positive tumors. In addition, BCL2 or BCL2L12-positive patients were found to be almost four times less likely to relapse or die in comparison to BCL2 or BCL2L12-negative patients, respectively. Multivariate analysis revealed that BCL2 and BCL2L12 might be used as independent prognostic biomarkers in breast cancer.

Adult↗

PubMed2002

MCL1 provides a window on the role of the BCL2 family in cell proliferation, differentiation and tumorigenesis.

The MCL1 gene (myeloid cell leukemia-1) was discovered serendipitously about a decade ago and proved to be a member of the emerging BCL2 gene family. Ongoing studies of this gene provide an interesting perspective on the role of the BCL2 family in transitions in cell phenotype. Specifically, gene products that influence cell viability as a major effect (eg MCL1, BCL2 and other family members) can act as key determinants in cell proliferation, differentiation and tumorigenesis. Although they do not have a direct role in proliferation/differentiation programs, these genes can either permit these programs to proceed or prevent them. Through such effects, the BCL2 family regulates the normal flow of cells through cycles of proliferation and along various pathways of differentiation. A model is presented suggesting that this is accomplished by sustaining or inhibiting viability at critical points in the cell lifecycle. These critical points represent windows of time during which cell fate transitions are effected. They can also be visualized as windows that open or close to promote or prevent continued progression along various cell fate pathways. The pattern of BCL2 family expression at these points allows for the proliferation differentiation, and continued viability of cell types that are needed, while aborting these processes for cells that are overabundant or no longer needed. The combined action of the various family members can therefore control the fate of cells, tissues and even the organism. This mechanism involving apoptosis-related genes is readily executable, and is poised to respond to external signals through the differential regulation of BCL2 family members. As such, it plays an important role in the maintenance of tissue homeostasis and function. Alterations that affect the BCL2 family impair the capacity to control the flow of cells through these critical points, and thereby 'leave the window open' for cell immortalization and cancer. Targeting this family may thus provide a means of inhibiting cancer development and inducing apoptosis in tumor cells.

Animals↗

PubMed1992

BCL2 oncogene translocation is mediated by a chi-like consensus.

Examination of 64 translocations involving the major breakpoint region (mbr) of the BCL2 oncogene and the immunoglobulin heavy chain locus identified three short (14, 16, and 18 bp) segments within the mbr at which translocations occurred with very high frequency. Each of these clusters was associated with a 15-bp region of sequence homology, the principal one containing an octamer related to chi, the procaryotic activator of recombination. The presence of short deletions and N nucleotide additions at the breakpoints, as well as involvement of JH and DH coding regions, suggested that these sequences served as signals capable of interacting with the VDJ recombinase complex, even though no homology with the traditional heptamer/spacer/nonamer (IgRSS) existed. Furthermore, the BCL2 signal sequences were employed in a bidirectional fashion and could mediate recombination of one mbr region with another. Segments homologous to the BCL2 signal sequences flanked individual members of the XP family of diversity gene segments, which were themselves highly overrepresented in the reciprocal products (18q-) of BCL2 translocation. We propose that the chi-like signal sequences of BCL2 represent a distinct class of recognition sites for the recombinase complex, responsible for initiating interactions between regions of DNA separated by great distances, and that BCL2 translocation begins by a recombination event between mbr and DXP chi signals. Since recombinant joints containing chi, not IgRSS, occur in brain cells expressing RAG-1 (Matsuoka, M., F. Nagawa, K. Okazaki, L. Kingsbury, K. Yoshida, U. Muller, D. T. Larue, J. A. Winer, and H. Sakano. 1991. Science [Wash. DC]. 254:81; reference 1), we further suggest that the product of this gene could mediate both BCL2 translocation and the first step of normal DJ assembly through the creation of chi joints, rather than signal or coding joints.

Base Sequence↗

PubMed2001

Bcl2-L-10, a novel anti-apoptotic member of the Bcl-2 family, blocks apoptosis in the mitochondria death pathway but not in the death receptor pathway.

By GenBank database searches and PCR, we have identified a novel human Bcl2-like gene, Bcl2-L-10, which contains conserved BH4, BH1 and BH2 domains but lacks BH3 domain. The Bcl2-L-10 gene has been assigned to chromosome 15q21.2. Transfection experiments demonstrated that Bcl2-L-10 can block apoptosis induced by interleukin-3 withdrawal and Bax expression, by prevention of cytochrome C release, caspase-3 activation and mitochondrial membrane potential collapse. Bcl2-L-10 cannot block TNFalpha-induced apoptosis. Furthermore, both the BH4 domain and the transmembrane domain of Bcl2-L-10 are necessary for its suppressive action on cell death. Our results demonstrated that Bcl2-L-10 is a newly detected anti-apoptotic member of the Bcl-2 family and that it blocks apoptosis in the mitochondrial death pathway but not in the death receptor pathway.

Amino Acid Sequence↗

PubMed2000

Regression of the decidualized mesometrium and decidual cell apoptosis are associated with a shift in expression of Bcl2 family members.

The purpose of this study was to determine whether regression of the decidua basalis (DB), which begins on Day 14 of pregnancy in the rat, results from an intrinsic program of apoptosis regulated by Bax and Bcl2. Expression of Bax and Bcl2 and the incidence of apoptosis were evaluated throughout gestation by Western blot analysis and detection of DNA fragments. Antiprogestin (RU486) was also administered during proliferation of DB to study progesterone regulation of Bax/Bcl2 balance. Bax, the pro-apoptotic protein, was expressed at a low level throughout pregnancy, whereas Bcl2, the pro-survival partner, was most abundantly expressed on Days 8 and 10, which are a time of proliferation and decidualization, and declined to barely detectable levels thereafter. These changes resulted in a 12-fold increase in the Bax:Bcl2 ratio on Day 17 as compared with Day 8 of pregnancy (P < 0.05). DNA laddering and in situ staining of DNA fragments first became visible on Day 14 and involved 2% of cells by Days 17 and 21 (P < 0.05). Treatment with RU486 on Day 9 enhanced Bax and suppressed Bcl2 within 6 h, increasing the Bax:Bcl2 ratio sixfold (P < 0.05). Apoptosis was minimal at 6 h and increased to 9% of cells by 24 h (P < 0.05). Thus, progesterone appears to regulate the apoptotic threshold of stromal cells by modulating Bax and Bcl2 expression.

Animals↗

PubMed2004

Characterization of the t(14;18) BCL2-IGH translocation in farmers occupationally exposed to pesticides.

Increasing incidence of non-Hodgkin's lymphoma have been associated repeatedly with farming occupation and particular attention focused on the role of pesticide exposure to potentially explain part of this trend. A genetic hallmark of non-Hodgkin's lymphoma is the presence of recurrent chromosomal translocations involving the immunoglobulin heavy chain gene. Of these, the t(14;18), which deregulates BCL2 expression and inhibits apoptosis, is the most frequent in follicular lymphoma and has been detected consistently in peripheral blood lymphocytes of healthy individuals. As BCL2-IGH translocation represents an early step of the malignant process, we evaluated the occurrence and molecular characteristics of BCL2-IGH translocation in 56 individuals occupationally exposed to pesticides in open field farming They were selected from a representative cohort of farmers with a well-defined assessment of pesticide exposure taking into account potential confounding factors, smoking, sunlight, and age. Our results suggest that occupational exposure to pesticides would increase BCL2-IGH prevalence together with the frequency of BCL2-IGH-bearing cells especially during the high pesticide use period. Distribution of BCL2 or IGH breakpoint positions seemed to be independent of pesticide exposure and was similar to those found in other healthy populations or lymphoma patients. Finally, these results provide additional evidence that BCL2-IGH translocation measurements could be a measure of acquired genetic instability in relation to genotoxic exposure in a gene directly relevant in term of lymphomagenesis.

Adolescent↗

PubMed2004

Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2.

Aberrant activation of the Hedgehog (HH)/GLI signaling pathway has been implicated in the development of basal cell carcinoma (BCC). The zinc finger transcription factors GLI1 and GLI2 are considered mediators of the HH signal in epidermal cells, although their tumorigenic nature and their relative contribution to tumorigenesis are only poorly understood. To shed light on the respective role of these transcription factors in epidermal neoplasia, we screened for genes preferentially regulated either by GLI1 or GLI2 in human epidermal cells. We show here that expression of the key antiapoptotic factor BCL2 is predominantly activated by GLI2 compared with GLI1. Detailed promoter analysis and gel shift assays identified three GLI binding sites in the human BCL2 cis-regulatory region. We found that one of these binding sites is critical for conferring GLI2-specific activation of the human BCL2 promoter and that the selective induction of BCL2 expression depends on the zinc finger DNA binding domain of GLI2. In vivo, GLI2 and BCL2 were coexpressed in the outer root sheath of hair follicles and BCC and in plasma cells that infiltrated BCC tumor islands. On the basis of the latter observation, we analyzed plasma cell-derived tumors and found strong expression of GLI2 and BCL2 in neoplastic cells of plasmacytoma patients, implicating HH/GLI signaling in the development of plasma cell-derived malignancies. The results reveal a central role for GLI2 in activating the prosurvival factor BCL2, which may represent an important mechanism in the development or maintenance of cancers associated with inappropriate HH signaling.

Base Sequence↗

PubMed2005

Effect of sphingosine on Ca2+ entry and mitochondrial potential of Jurkat T cells--interaction with Bcl2.

Triggers of Jurkat T cell apoptosis include sphingosine and ceramide. Sphingosine and ceramide further inhibit capacitative Ca2+ entry (ICRAC), an effect leading to inactivation but not death of Jurkat T cells. Mitochondria are key organelles in the machinery leading to apoptosis and on the other hand have been shown to participate in the regulation of Ca2+ entry. The present experiments were performed to explore whether treatment of Jurkat T cells with sphingosine leads to apoptosis and reduced Ca2+ entry and whether those effects are sensitive to expression of the antiapoptotic protein Bcl2, localized in the outer mitochondrial membrane. Exposure of Jurkat T cells to 10 microM spingosine was according to DiOC6 fluorescence followed by mitochondrial depolarization and according to Fura-red/Fluo-3 fluorescence followed by decreased capacitative Ca2+ entry. Mitochondrial depolarization was significantly delayed in cells overexpressing wild type Bcl2 or Bcl2 targeted to the mitochondrial membrane, whereas no significant influence on mitochondrial depolarization was observed in cells expressing Bcl2 lacking the membrane targeting motif or Bcl2 targeted to the endoplasmatic reticulum. In contrast to mitochondrial potential, the blunting of capacitative Ca2+ entry following sphingosine treatment was not sensitive to mitochondrial Bcl2 expression. In conclusion sphingosine exposure leads to both, mitochondrial depolarization and inhibition of capacitative Ca2+ entry. Mitochondrial Bcl2 reverses the effect on mitochondria but not on Ca2+ entry and thus leads to dissociation of those two sequelae of sphingosine treatment.

Apoptosis↗

PubMed2003

Immunohistochemical status of p53, MDM2, bcl2, bax, and ER in invasive ductal breast carcinoma in Tunisian patients.

TP53 gene alterations have been associated with sporadic breast cancer. To assess the role of p53 in invasive ductal carcinoma (IDC) of the breast among Tunisian patients, p53 protein status was studied by immuno-histochemical analysis. The p53 protein was expressed in 41 of 70 (58%) tumors. Study of the status of its target gene expression showed that MDM2 was overexpressed in 43 tumors (61%), bcl2 in 29 (41%), and bax in only 9 (12%). Estrogen receptor (ER) was detected in 38 tumor tissues (54%). The accumulated p53 was significantly associated with MDM2-positive, bcl2-negative, and ER-negative tumors (P = 0.024, P = 0.000027, and P = 0.000008, respectively), whereas with bax the correlaton was not significant. Bcl2 immunostaining displayed a positive correlation with ER (P = 0.001). A significantly higher fraction of p53-positive cells was observed in ER-negative SBRII-SBRIII tumors than in ER-positive SBRI-SBRII tumors (P = 0.000066). bcl2-positive tumors were significantly correlated with ER-positive/SBRI-SBRII tumors (P = 0.007), but negatively correlated with p53/bax (P = 0000004). MDM2 immunostaining displayed the same phenotype as p53 in the correlation with bcl2 and ER (P = 0.003), strengthened by significant associations between MDM2-positive/p53-positive and bcl2-negative or ER-negative, respectively (P = 0.00005 and P = 0.000001, respectively). MDM2-positive cells were significantly correlated with the p53-positive/bax-negative phenotype (P = 0.04). These results suggest that p53 accumulated in these tumor tissues is associated with bad prognostic markers (ER-negative, SBRIII) of IDC. MDM2 overexpression might be responsible for the accumulated p53 value in IDC. Regulation of the apoptotic process is involved in IDC; bcl2 is associated with a good prognostic marker (ER-positive and SBRI-II), whereas the regulation of bax is complex and does not necessarily correlate with the overexpression of p53.

Adult↗

PubMed2000

Epithelial cells release proinflammatory cytokines and undergo c-Myc-induced apoptosis on exposure to filarial parasitic sheath protein-Bcl2 mediates rescue by activating c-H-Ras.

Circulating filarial proteins elicit strong immunologic reactions in humans leading to the chronic manifestations in human lymphatic filariasis such as lymphatic occlusion, fibrosis, edema, and in some cases, tropical pulmonary eosinophilia. Our earlier studies, in vitro, conclusively prove that filarial parasitic sheath proteins induce apoptosis in HEp2 cells, an epithelial cell line, by a pathway inhibitable by bcl2. The present findings provide evidence that c-myc activation triggers apoptosis in HEp2 cells and that it is also responsible for the burst of abortive proliferation at 6 d of treatment of HEp2 bcl2 cells that overexpress bcl2, with filarial parasitic sheath protein, demonstrating the interplay between the two genes c-myc and bcl2, wherein bcl2 acts by restoring the prosurvival signal to c-myc and keeping its apoptotic tendency in check. This study also indicates that bcl2 upregulates c-H-ras, engaging ras to bring about the suppression of apoptosis through protein tyrosine kinase elevation, thus promoting the survival of the HEp2 bcl2 cells. In addition to the activation of these "signal switches," we also observe that these cells release cytokines like IL-6 and IL-8 through the upregulation of c-fos, when exposed to filarial parasitic sheath protein, reflecting on the immunomodulatory capacity of the epithelium to elicit a host immune response by setting up a chemotactic gradient, attracting inflammatory cells to the site of infection.

Animals↗

PubMed2000

Topographic expression of p21WAF1/SDI1/CIP1, bcl2, and p53 is altered at the early stage of colorectal carcinogenesis.

We analyzed the expression of p21, bcl2, and p53 in normal and different pathologic mucosa of the human colorectum using immunohistochemistry and cold polymerase chain reaction-single strand conformation polymorphism. The topography of normal mucosa showed; bcl2 and p53 expression restricted to basal epithelial cells and p21 expressed only in superficial epithelial cells. This topographic expression was altered in hyperplastic polyps and adenomas. Hyperplastic polyps revealed absence of or weak bcl2 expression and strong p21 expression without topography. In adenomas, whereas bcl2 expression increased and extended to parabasal and superficial dysplastic epithelium, the increase of p21 expression was limited to surface dysplastic epithelium. p53 was weakly expressed throughout the full thickness of dysplastic epithelium. Bcl2 expression in adenomas was stronger than in carcinomas; p53 expression was converse and p21 expression was variable. In carcinomas, this topographic expression was largely abrogated but p53 mutation (36%) was more frequent than in adenomas (2%). In carcinomas, p21 and p53 expression correlated inversely, but there was no relationship with bcl2. These results suggest that there is precisely ordered topographic pattern of p21, bcl2, and wild p53 expression in normal colorectal cells, but this becomes disordered during the early stage of colorectal carcinogenesis.

Colorectal Neoplasms↗