Biomedical subjects

Masao Seto

Publications and source records attributed to Masao Seto.

At least 19 recordsLinked to original sources

PubMed2007

CD10-MUM1+ follicular lymphoma lacks BCL2 gene translocation and shows characteristic biologic and clinical features.

CD10 and MUM1 are representative B cell differentiation markers. Follicular lymphoma (FL) is usually positive for CD10 and negative for MUM1. In this study, however, we compared 22 FLs with peculiar phenotype CD10-MUM1+ with 119 typical CD10+MUM1- FLs. All CD10-MUM1+ FL patients exhibited follicular structure with follicular dendritic meshwork, and a high rate of somatic hypermutation and ongoing mutation, similar to typical FL. However, CD10-MUM1+ FLs were encountered frequently in the elderly compared with CD10+MUM1- typical FLs (67.0 versus 58.7 years, P < .01), showed high grade (grade 3A or 3B) morphology (91% versus 17%, P < .001), diffuse proliferation (59% vs 19%, P < .001), and lacked BCL2/IGH translocation (5% versus 92.5%, P < .001), which is the most characteristic aberration in FL, and 88% showed BCL6 gene abnormalities (translocation or amplification). Our results indicate that CD10-MUM1+ FL is different from typical FL with respect to biologic and clinical features.

Aged↗

PubMed2006

Expression profiling analysis of the CD5+ diffuse large B-cell lymphoma subgroup: development of a CD5 signature.

Diffuse large B-cell lymphoma (DLBCL) accounts for 30% of non-Hodgkin's lymphomas and is known to comprise heterogeneous groups. We previously reported that CD5+ DLBCL is a clinically distinct subgroup of these tumors that is associated with poor prognosis. In our current study, we have used gene expression profiling technology in an attempt to identify new markers and to further characterize the biological features of CD5+ DLBCL. Candidate genes, which showed the greatest difference in expression between 22 CD5+ and 26 CD5- DLBCL cases, were selected from our screening and subjected to clustering analysis. This resulted in identification of a specific mRNA profile (a CD5 signature) for CD5+ DLBCL. The CD5 signature included downregulated extracellular matrix genes such as POSTN, SPARC, COL1A1, COL3A1, CTSK, MMP9 and LAMB3, and comprised upregulated genes including TRPM4. We tested this CD5 signature for its potential use as a relevant marker for CD5+ DLBCL and found that it did indeed recognize this subgroup. The tumors identified by the CD5 signature contained most of the CD5+ DLBCL cases and some CD5- DLBCL cases. Moreover, the subgroup of cases with this CD5 signature showed a poorer prognosis. The subsequent application of the CD5 signature to the analysis of an independent series of DLBCL microarray data resulted in identification of a subgroup of DLBCL cases with a similar clinical outcome, further suggesting that the CD5 signature can be used as a clinically relevant marker of this disease.

Biomarkers, Tumor↗

PubMed2006

Identification of subtype-specific genomic alterations in aggressive adult T-cell leukemia/lymphoma.

Aggressive adult T-cell leukemia/lymphoma (ATLL) such as acute and lymphoma types are fatal diseases with poor prognosis. Although these 2 subtypes feature different clinicopathologic characteristics, no detailed comparative analyses of genomic/genetic alterations have been reported. We performed array-based comparative genomic hybridization for 17 acute and 49 lymphoma cases as well as real-time quantitative polymerase chain reaction (PCR) to identify the target genes of recurrently amplified regions. Comparison of the genome profiles of acute and lymphoma types revealed that the lymphoma type had significantly more frequent gains at 1q, 2p, 4q, 7p, and 7q, and losses of 10p, 13q, 16q, and 18p, whereas the acute type showed a gain of 3/3p. Of the recurrent high-level amplifications found at 1p36, 6p25, 7p22, 7q, and 14q32 in the lymphoma type, we were able to demonstrate that CARMA1 is a possible target gene of the 7p22 amplification for the lymphoma type but not for the acute type. Furthermore, we found BCL11B overexpression in the acute type regardless of the 14q32 gain/amplification, but no or low expression of the gene in the lymphoma type. These results suggest that acute and lymphoma types are genomically distinct subtypes, and thus may develop tumors via distinct genetic pathways.

Adult↗

PubMed2006

Genomewide array-based comparative genomic hybridization analysis of acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is typically associated with the t(15;17) that generates the PML-RARA fusion protein. Animal models have shown that although the fusion protein is necessary, it is insufficient for the development of APL, implying that additional mechanisms are responsible for full-blown leukemia. The mutation of specific genes has been implicated in leukemogenesis; however, alterations in gene copy number have not been well investigated. Here, we applied the genomewide array-comparative genomic hybridization technique to 30 APL clinical samples and 2 APL cell lines. It was found that (1) approximately half the clinical samples (14 of 30 APL cases) had no detectable chromosomal imbalances; and (2) the remaining 16 cases, including the cell lines, exhibited recurrent chromosomal imbalances, such as loss of 1p36, 2p11, 16p, and 17p, and gain of 8p, 8q, and 13q. These results suggest that chromosomal imbalances are largely absent in APL, although some nonrandom chromosomal imbalances could be linked to the development of APL in a limited number of cases.

Adolescent↗

PubMed2006

Characterization of target genes at the 2p15-16 amplicon in diffuse large B-cell lymphoma.

Amplification of 2p has been observed as a recurrent alteration in diffuse large B-cell lymphoma (DLBCL). Whereas two candidate oncogenes, REL and BCL11A, have been investigated as targets for 2p amplification, the question remains as to whether the true target gene in the amplicon is REL, BCL11A or both. We previously identified frequent genomic gains of chromosomal 2p in 25 out of 99 DLBCL cases by means of genome-wide array comparative genomic hybridization (CGH). All of these 25 cases included recurrent copy number gain at 2p15-16. In the study presented here, cases were analyzed in greater detail by means of contig bacterial artificial chromosome (BAC) array CGH for the 4.5-Mb region at 2p15-16, which contained 33 BAC clones. We confined the minimal common region to 500-kb in length, where only the candidate oncogene REL, and not BCL11A, is located. Real-time quantitative PCR was carried out to investigate the correlation between genomic gain and expression. It showed a significant correlation for both genes, indicating that these two genes are common targets for the 2p15-16 amplicon. However, given the fact that REL is more frequently amplified than BCL11A, the REL gene may play a more important role than BCL11A in the pathogenesis of DLBCL.

Chromosomes, Artificial, Bacterial↗

PubMed2005

Identification of CCND3 and BYSL as candidate targets for the 6p21 amplification in diffuse large B-cell lymphoma.

PURPOSE: Increases in gene dosage through DNA amplification represents a common feature of many tumors and can result in the up-regulation of tumor-promoting genes. Our recent genome-wide, array-based comparative genomic hybridization analysis of 66 cases of diffuse large B-cell lymphoma found that genomic gain of 6p21 was observed in as many as 17 cases, including 14 cases with low-level copy number gain and three cases with high-level copy number gains (amplifications). EXPERIMENTAL DESIGN AND RESULTS: To identify the target gene(s) for 6p21 amplification, we constructed a detailed amplicon map at the region of genomic amplification with the aid of high-resolution contig array-based comparative genomic hybridization glass slides, consisting of contiguously ordered bacterial artificial chromosome/P1-derived artificial chromosome clones covering 3 Mb throughout the 6p21 amplification region. Alignment of the amplifications identified a minimally overlapping 800 kb segment containing 15 genes. Quantitative expression analysis of the genes from both patient samples and the SUDHL9 cell line revealed that CCND3 and BYSL (1.9 kb telomeric to the CCND3 gene locus) are the targets of 6p21 genomic gain/amplification. CONCLUSIONS: Although it is known that t(6;14)(p21;q32) induces aberrant overexpression of CCND3 in B-cell malignancies, we were able to show that CCND3, which encodes the cyclin D family member protein that controls the G1-S phase of cell cycle regulation, can also be a target of genomic gain/amplification. Overexpression of CCND3 through genomic amplification is likely to lead to aberrant cell cycle control, although the precise biological role of BYSL with respect to tumorigenesis remains to be determined.

Blotting, Northern↗

PubMed2005

MALT1 contains nuclear export signals and regulates cytoplasmic localization of BCL10.

MALT1, BCL10 (B-cell lymphoma 10), and API2 (apoptosis inhibitor 2)-MALT1 are key molecules in mucosa-associated lymphoid tissue (MALT) lymphomagenesis. We previously reported that MALT1 and API2-MALT1 were localized only in cytoplasm, where we suggested that both molecules were likely to be active. In the study presented here, we further examined the localization-determining region by generating various mutants and were able to demonstrate that there were nuclear export signal (NES)-containing domains in the MALT1 C-terminal region. The use of leptomycin B, an NES-specific inhibitor, demonstrated that both MALT1 and API2-MALT1 were predominantly retained in the nuclei, indicating that these molecules were shuttling between nucleus and cytoplasm in an NES-dependent manner. It was also found that MALT1 was involved in the nuclear export of BCL10, which is originally localized in both nucleus and cytoplasm. These results correlate well with the nuclear BCL10 expression pattern in both t(1;14) and t(11;18) MALT lymphomas. The nucleocytoplasmic shuttling of MALT1 and BCL10 complex may indicate that these molecules are involved not only in the nuclear factor kappaB (NF-kappaB) pathway but also in other biologic functions in lymphocytes.

Adaptor Proteins, Signal Transducing↗

PubMed2005

API2-MALT1 fusion protein induces transcriptional activation of the API2 gene through NF-kappaB binding elements: evidence for a positive feed-back loop pathway resulting in unremitting NF-kappaB activation.

t(11;18)(q21;q21) is a characteristic as well as the most frequent chromosomal translocation in mucosa-associated lymphoid tissue (MALT) type lymphoma, and this translocation results in a fusion transcript, API2-MALT1. Although API2-MALT1 has been shown to enforce activation of NF-kappaB signaling, the transcriptional target genes of this fusion protein remains to be identified. Our analyses of the API2-MALT transfectants suggested that one of the target genes may be the apoptotic inhibitor API2 gene. Luciferase reporter assays with deletion and mutational constructs of the API2 promoter and electrophoretic mobility shift assays established that API2-MALT1 induces transcriptional activation of the API2 gene through two NF-kappaB binding elements. Moreover, supershift experiments indicated that these elements are recognized by the NF-kappaB p50/p65 heterodimer. Taken together, our results strongly indicated that API2-MALT1 possesses a novel mechanism of self-activation by up-regulating its own expression in t(11;18)(q21;q21)-carrying MALT lymphomas, highlighting a positive feedback-loop pathway resulting in unremitting NF-kappaB activation.

Binding Sites↗

PubMed2005

Comparison of genome profiles for identification of distinct subgroups of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) comprises molecularly distinct subgroups such as activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCLs. We previously reported that CD5(+) and CD5(-)CD10(+) DLBCL constitute clinically relevant subgroups. To determine whether these 2 subgroups are related to ABC and GCB DLBCLs, we analyzed the genomic imbalance of 99 cases (36 CD5(+), 19 CD5(-)CD10(+), and 44 CD5(-)CD10(-)) using array-based comparative genomic hybridization (CGH). Forty-six of these cases (22 CD5(+), 7 CD5(-)CD10(+), and 17 CD5(-)CD10(-)) were subsequently subjected to gene-expression profiling, resulting in their division into 28 ABC (19 CD5(+) and 9 CD5(-)CD10(-)) and 18 GCB (3 CD5(+), 7 CD5(-)CD10(+), and 8 CD5(-)CD10(-)) types. A comparison of genome profiles of distinct subgroups of DLBCL demonstrated that (1) ABC DLBCL is characterized by gain of 3q, 18q, and 19q and loss of 6q and 9p21, and GCB DLBCL is characterized by gain of 1q, 2p, 7q, and 12q; (2) the genomic imbalances characteristic of the CD5(+) and CD5(-)CD10(+) groups were similar to those of the ABC and GCB types, respectively. These findings suggest that CD5(+) and CD5(-)CD10(+) subgroups are included, respectively, in the ABC and GCB types. Finally, when searching for genomic imbalances that affect patients' prognosis, we found that 9p21 loss (p16(INK4a) locus) marks the most aggressive type of DLBCL.

Adult↗

PubMed2005

Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM.

Mantle cell lymphoma (MCL) is characterized by 11q13 chromosomal translocation and CCND1 overexpression, but additional genomic changes are also important for lymphomagenesis. To identify the genomic aberrations of MCL at higher resolutions, we analysed 29 patient samples and seven cell lines using array-based comparative genomic hybridization (array CGH) consisting of 2348 artificial chromosome clones, which cover the whole genome at a 1.3 mega base resolution. The incidence of identified genomic aberrations was generally higher than that determined with chromosomal CGH. The most frequent imbalances detected by array CGH were gains of chromosomes 3q26 (48%), 7p21 (34%), 6p25 (24%), 8q24 (24%), 10p12 (21%) and 17q23 (17%), and losses of chromosomes 2p11 (83%), 11q22 (59%), 13q21 (55%), 1p21-p22 (52%), 13q34 (52%), 9q22 (45%), 17p13 (45%), 9p21 (41%), 9p24 (41%), 6q23-q24 (38%), 1p36 (31%), 8p23 (34%), 10p14 (31%), 19p13 (28%), 5q21 (21%), 22q12 (21%), 1q42 (17%) and 2q13 (17%). Our analyses also detected several novel recurrent regions of loss located at 1p36, 1q42.2-q43, 2p11.2, 2q13, 17p13.3 and 19p13.2-p13.3, as well as recurrent regions of homozygous loss such as 2p11 (Ig(kappa)), 2q13 and 9p21.3-p24.1 (INK4a/ARF). Of the latter, we investigated the 2q13 loss, which led to identification of homozygous deletions of the proapoptotic gene BIM. The high-resolution array CGH technology allowed for the precise identification of genomic aberrations and identification of BIM as a novel candidate tumor suppressor gene in MCL.

Aged↗

PubMed2005

Genome-wide array-based comparative genomic hybridization of natural killer cell lymphoma/leukemia: different genomic alteration patterns of aggressive NK-cell leukemia and extranodal Nk/T-cell lymphoma, nasal type.

Natural killer (NK) cell lymphomas/leukemias are highly aggressive lymphoid malignancies, but little is known about their genomic alterations, and thus there is an urgent need for identification and analysis of NK cell lymphomas/leukemias. Recently, we developed our own array-based comparative genomic hybridization (array CGH) with an average resolution of 1.3 Mb. We performed an array CGH analysis for 27 NK-cell lymphoma/leukemia cases that were classified into two disease groups based on the World Health Organization Classification (10 aggressive NK-cell leukemia cases and 17 extranodal NK/T-cell [NK/T] lymphomas, nasal type). We identified the differences in the genomic alteration patterns of the two groups. The recurrent regions characteristic of the aggressive NK-cell leukemia group compared with those of the extranodal NK/T lymphoma, nasal-type group, were gain of 1q and loss of 7p15.1-p22.3 and 17p13.1. In particular, gain of 1q23.1-24.2 (P = 0.041) and 1q31.3-q44 (P = 0.003-0.047), and loss of 7p15.1-p22.3 (P = 0.012-0.041) and 17p13.1 (P = 0.012) occurred significantly more frequently in the former than in the latter group. Recurrent regions characteristic of the extranodal NK/T lymphoma, nasal-type group, compared with those of the other group were gain of 2q, and loss of 6q16.1-q27, 11q22.3-q23.3, 5p14.1-p14.3, 5q34-q35.3, 1p36.23-p36.33, 2p16.1-p16.3, 4q12, and 4q31.3-q32.1. Our results can be expected to provide further insights into the genetic basis of lymphomagenesis and the clinicopathologic features of NK-cell lymphomas/leukemias.

Adolescent↗

PubMed2005

BMI-1 is highly expressed in M0-subtype acute myeloid leukemia.

Recent studies have suggested that one of the polycomb group genes, BMI-1, has an important role in the maintenance of normal and leukemic stem cells by repressing the INK4a/ARF locus. Here, we quantitatively examined BMI-1 expression level in samples from patients with acute myeloid leukemia (AML) and other hematologic malignancies. Moderate to high BMI-1 expression was detected in AML patients, and the BMI-1 expression levels in AML samples were significantly higher than in normal bone marrow controls (P = .0011). Specimens of French-American-British classification subtype M0 showed higher relative expression of the BMI-1 transcript (median, 390.2 3 10(-3)) than the other subtypes (median, 139.0 3 10(-3)) (P < .0001). Leukemia other than AML showed low to moderate expression. INK4a-ARF transcript expression tended to be inverse proportion to that of BMI-1. In an M0 patient with a high BMI-1 transcript level, the INK4a-ARF transcript level fell promptly and maintained a low value after the patient achieved complete remission. These results indicated that a subgroup of M0 patients has a high expression level of polycomb group gene BMI-1, which may contribute to leukemogenesis.

Acute Disease↗

PubMed2005

Differential expression of cytokines, chemokines and their receptors in follicular lymphoma and reactive follicular hyperplasia: assessment by complementary DNA microarray.

Follicular lymphoma (FL) is pathologically categorised as a low-grade B-cell lymphoma and histopathologically shows follicular proliferation of neoplastic B cells. In the neoplastic follicles of FL, the presence of T cells, macrophages and follicular dendritic cells (FDCs) suggests that these cells may promote a favourable environment for the growth of FL cells. Because FL cells are generally associated with FDCs, FDCs may be considered an important source of cytokines and chemokines. FDCs form the framework for germinal centres and also provide networks for nodules of FL. To evaluate the gene expression in neoplastic follicles of FL and reactive follicles of reactive follicular hyperplasia (RFH), we performed gene expression profiling of FL (n=5) and RFH (n=5) using complementary DNA (cDNA) microarray of cytokines/chemokines and their receptors. FL and RFH exhibited a diffuse down-regulated profile compared with normal peripheral blood cells, which were used as controls, although some genes displayed up-regulated profiles. Hierarchical clustering analysis separated FL and RFH into two distinct groups based on their gene expression profiles. FL cases exhibited significantly higher expression of interleukin 3 receptor alpha (IL-3Ralpha) than RFH. Immunohistochemically, neoplastic follicles of FL frequently expressed IL-3Ralpha, especially in FDCs, but not in FL cells. However, IL-3Ralpha expression was rare or weak in the reactive follicles of RFH. These findings suggest the importance of the micro-environment for FL cell growth. Further studies of cDNA microarray should provide new insight into the molecular pathology of FL and may allow the design of improved therapies.

Adult↗

PubMed2005

[Antiapoptotic functions of the retrovirally transferred API2-MALT1 gene].

t(11 ; 18)(q21 ; q21) is a specific chromosomal aberration in mucosa-associated lymphoid tissue (MALT) lymphoma, and produces chimeric transcript Apoptosis Inhibitor 2 (API2)-MALT1. Although it is known that API2 has an antiapoptotic effect, it is still unclear whether this also applies to API2-MALT1. To investigate its effects against various apoptotic stimuli, API2-MALT1 was expressed by means of retroviral infection on the epithelial cell line HeLa and the murine Pro-B cell line Ba/F3. On both these cell lines, API2-MALT1 was found to cause a significant reduction in UV-induced apoptosis. The apoptosis induced by doxorubicin was also inhibited by API2-MALT1, but not that induced by IL-3 withdrawal from Ba/F3. These findings suggest that API2-MALT1 has an antiapoptotic effect on both epithelial and lymphoid cells and that this effect depends on the apoptotic stimulus.

Animals↗

PubMed2004

Contig array CGH at 3p14.2 points to the FRA3B/FHIT common fragile region as the target gene in diffuse large B-cell lymphoma.

Deletions of the 3p arm have been detected in various solid tumors, but no study to date has investigated this deletion in diffuse large B-cell lymphoma (DLBCL). Recently, we demonstrated that 3p14.2 was deleted in approximately 30% of DLBCL cases by use of a genome-wide array-comparative genomic hybridization (CGH). For a more detailed examination of the genomic losses at 3p14.2, here we made use of contig BAC array for 3p14.2, and found that 12 DLBCL samples displayed losses. All of the deleted regions were located within the fragile histidine triad (FHIT) gene, and the most frequent region of loss was mapped to 0.4 Mbp of the region encompassing the introns 4 and 5 and exon 5 of the FHIT gene. Concomitant analysis of transcripts showed that the FHIT gene was aberrantly transcribed in 31% of the DLBCL samples examined and that the lost exons of the aberrant transcripts were correlated with genomic deletions. These findings indicate that (1) loss of genomic material at 3q14.2 is responsible for exon losses of the FHIT gene, and (2) genomic loss of the FHIT gene is one of the causes of the generation of aberrant transcripts.

Acid Anhydride Hydrolases↗

PubMed2004

Genome-wide array-based comparative genomic hybridization of diffuse large B-cell lymphoma: comparison between CD5-positive and CD5-negative cases.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma and exhibits aggressive and heterogeneous clinical behavior. To genetically characterize DLBCL, we established our own array-based comparative genomic hybridization and analyzed a total of 70 cases [26 CD-positive (CD5+) DLBCL and 44 CD5-negative (CD5-) DLBCL cases]. Regions of genomic aberrations observed in >20% of cases of both the CD5+ and CD5- groups were gains of 1q21-q31, 1q32, 3p25-q29, 5p13, 6p21-p25, 7p22-q31, 8q24, 11q23-q24, 12q13-q21, 16p13, 18, and X and losses of 1p36, 3p14, 6q14-q25, 6q27, 9p21, and 17p11-p13. Because CD5 expression marks a subgroup with poor prognosis, we subsequently analyzed genomic gains and losses of CD5+ DLBCL compared with those of CD5-. Although both groups showed similar genomic patterns of gains and losses, gains of 10p14-p15 and 19q13 and losses of 1q43-q44 and 8p23 were found to be characteristic of CD5+ DLBCL. By focusing on the gain of 13q21-q34 and loss of 1p34-p36, we were also able to identify prognostically distinct subgroups among CD5+ DLBCL cases. These results suggest that array-based comparative genomic hybridization analysis provides a platform of genomic aberrations of DLBCL both common and specific to clinically distinct subgroups.

CD5 Antigens↗

PubMed2004

Modeling first-hit functions of the t(12;21) TEL-AML1 translocation in mice.

The t(12;21) translocation, which generates the TEL-AML1 (ETV6-RUNX1) fusion gene, is the most common structural chromosome change in childhood cancer and is exclusively associated with the common B cell precursor subset of acute lymphoblastic leukemia (ALL). Evidence suggests that the translocation usually occurs in utero during fetal hemopoiesis and most probably constitutes an initiating or first-hit mutation that is necessary but insufficient for the development of overt, clinical leukemia. The mechanism by which TEL-AML1 contributes to this early stage of leukemogenesis is unknown. To address this question we have analyzed hemopoiesis in mice syngeneically transplanted with TEL-AML1-transduced bone marrow stem cells. TEL-AML1 expression was associated with an accumulation/expansion of primitive c-kit-positive multipotent progenitors and a modest increase in myeloid colony-forming cells. TEL-AML1 expression was, however, permissive for myeloid differentiation. Analysis of B lymphopoiesis revealed an increase in early, pro-B cells but a differentiation deficit beyond that stage, resulting in reduced B cell production in the marrow. TEL-AML1-positive B cell progenitors exhibited reduced expression of the surrogate light-chain component lambda5 and the IL-7 receptor, both of which may contribute to impedance of differentiation in vivo and account for their reduced in vitro clonogenicity in IL-7. A selective differentiation deficit of B lineage progenitors (i) is consistent with the phenotype of TEL-AML1-associated leukemia in children and (ii) provides a potential mechanism for the protracted preleukemic state that often precedes ALL. These results provide mechanistic insight into the role of the t(12;21) translocation in the initiation of common B cell precursor ALL.

Animals↗

PubMed2004

Antiapoptotic function of apoptosis inhibitor 2-MALT1 fusion protein involved in t(11;18)(q21;q21) mucosa-associated lymphoid tissue lymphoma.

t(11;18)(q21;q21) is a characteristic chromosomal translocation in mucosa-associated lymphoid tissue (MALT) type lymphoma, and this translocation results in fusion transcript of apoptosis inhibitor 2 (API2), also known as c-IAP2, and MALT translocation gene 1 (MALT1). Although the API2-MALT1 fusion protein has been shown to enforce activation of nuclear factor kappaB signaling, its precise role in the apoptotic signaling pathway remains to be established. To identify proteins that bind the API2-MALT1 protein, we used coimmunoprecipitation and SDS-PAGE, followed by liquid chromatography-electrospray ionization tandem mass spectrometry. As a result, three important regulators of apoptosis, Smac, HtrA2, and TRAF2, and three other proteins were identified as potential API2-MALT1-binding proteins. Immunoprecipitation analyses verified that API2-MALT1 indeed binds to both exogeneous and endogeneous Smac proteins. It is especially noteworthy that stably transfected API2-MALT1 significantly suppressed both UV- and etoposide-induced apoptosis in HeLa cells, thus demonstrating for the first time that API2-MALT1 indeed possesses antiapoptotic function. Furthermore, API2-MALT1 significantly suppressed Smac-promoted apoptosis in UV-irradiated HeLa cells. Thus, our results provide direct experimental evidence that API2-MALT1 can confer resistance to apoptosis, at least in part, by neutralizing apoptosis promoted by Smac.

Amino Acid Sequence↗