Proapoptotic activity of ITM2Bs, a BH3-only protein induced upon IL-2-deprivation which interacts with Bcl-2

Fleischer, Aarne; Ayllón, Verónica; Dumoutier, Laure; Renauld, Jean‐Christophe; Rebollo, Angelita

doi:10.1038/sj.onc.1205464

Cited by 38 publications

(40 citation statements)

References 30 publications

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“…These data further supported the hypothesis that genes located near the model tumor suppressor, RB1, subsequently referred to by us as FR genes, may significantly contribute to the development of bladder cancer. By analyzing the predicted functions of their encoded proteins, we decided to concentrate our initial efforts on the two nearest neighbor genes flanking RB1, namely ITM2B, which encodes a mitochondrial membrane protein with a Bcl-2 homology 3 (BH3) domain (15), CHC1L (RCBTB2), which encodes a guanine nucleotide exchange factor protein for the ras-related GTPase (16), and P2RY5 located within intron 17 of RB1, which encodes a G protein-coupled receptor (17).…”

Section: Rb1mentioning

confidence: 99%

Forerunner genes contiguous to RB1 contribute to the development of in situ neoplasia

Lee¹,

Lee²,

Majewski³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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We used human bladder cancer as a model system and the whole-organ histologic and genetic mapping strategy to identify clonal genetic hits associated with growth advantage, tracking the evolution of bladder cancer from intraurothelial precursor lesions. Six putative chromosomal regions critical for clonal expansion of intraurothelial neoplasia and development of bladder cancer were identified by using this approach. Focusing on one of the regions, which includes the model tumor suppressor RB1, we performed allelotyping of single-nucleotide polymorphic sites and identified a 1.34-Mb segment around RB1 characterized by a loss of polymorphism associated with the initial expansion of in situ neoplasia. This segment contains several positional candidate genes referred to by us as forerunner genes that may contribute to such expansion. We subsequently concentrated our efforts on the two neighbor genes flanking RB1, namely ITM2B and CHC1L, as well as P2RY5, which is located inside RB1. Here, we report that ITM2B and P2RY5 modulated cell survival and were silenced by methylation or point mutations, respectively, and thus by functional loss may contribute to the growth advantage of neoplasia. We also show that homozygous inactivation of P2RY5 was antecedent to the loss of RB1 during tumor development, and that nucleotide substitutions in P2RY5 represent a cancer predisposing factor.bladder cancer ͉ single-nucleotide polymorphic sites ͉ whole-organ histologic and genetic mapping M any common epithelial cancers, including those arising in the bladder, begin as clonal in situ expansion of neoplastic cells, which show no or minimal deviation from the normal phenotype (1-4). Such lesions often form plaques involving large areas of the affected mucosa, and their expansion precedes the development of microscopically recognizable dysplasia or carcinoma in situ (4, 5). Identification of chromosomal regions associated with the initial expansion of neoplasia is a requisite for more specific studies of their positional candidate genes that may drive the initial clonal expansion of neoplasia.We have used an approach referred to as whole-organ histologic and genetic mapping (WOHGM) to identify clonal hits associated with growth advantage, tracking the evolution of human bladder cancer from occult in situ lesions to invasive disease on a total genomic scale (6-8). Human bladder carcinoma was used as a model of common epithelial malignancy that develops by progression of microscopically recognizable intraurothelial preneoplastic lesions ranging from mild dysplasia to carcinoma in situ (5). Bladder cancer was also selected because it is close to an ideal model human tumor to study the early events of carcinogenesis due to simple anatomy of the organ and the ease in mapping preneoplastic conditions geographically across the entire mucosa of cystectomy specimens (9-11).In this paper, we begin by presenting the identification of the six critical chromosomal regions that may contain genes driving the development of bladder cancer. Then, we f...

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Section: Rb1mentioning

confidence: 99%

Forerunner genes contiguous to RB1 contribute to the development of in situ neoplasia

Lee¹,

Lee²,

Majewski³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…DLC1 and AKAP12/gravin were reported to be either deleted or downregulated in human cancer, whereas restoration of their expression induced apoptosis (Yuan et al, 2003;Choi et al, 2004). ITM2B is a known regulator of cell death that promotes apoptosis and interacts with BCL2 (Fleischer et al, 2002). Therefore, upregulation of these genes may contribute to growth inhibition in ATRA-treated Wilms tumor cells.…”

Section: Genes Involved In Cell Proliferation and Matrix Remodelingmentioning

confidence: 99%

All-trans retinoic acid treatment of Wilms tumor cells reverses expression of genes associated with high risk and relapse in vivo

Zirn

Samans

Spangenberg³

et al. 2005

Oncogene

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“…Costimulation enhances T cell viability not only by inducing IL-2 but also by upregulating the antiapoptotic proteins Bcl-x L (11)(12)(13) and to a lesser extent Bcl-2 (14 -16). Indeed, deprivation of IL-2 from stimulated T cells causes the up-regulation of proapoptotic proteins and induces apoptosis (17). Thus, CD28 costimulation enhances the proliferative expansion of T cells activated through the TCR and also increases T cell survival by inducing Bcl-x L and Bcl-2.…”

mentioning

confidence: 99%

Antiapoptotic Microenvironment of Acute Myeloid Leukemia

Milojković¹,

Devereux²,

Westwood³

et al. 2004

The Journal of Immunology

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We showed previously that tumor-derived supernatant (TSN) from acute myeloid leukemia (AML) myeloblasts inhibits peripheral blood T cell activation and proliferation, rendering the T cells functionally incompetent. We show here that the AML TSN also significantly delays apoptosis of both resting and stimulated T cells, as judged by reduction in annexin V/propidium iodide staining. In addition, we show that this is not unique to T cells and that AML TSN inhibits apoptosis of peripheral B cells, neutrophils, and monocytes. Furthermore, it also enhances the survival of other AML myeloblasts with lower viability. Investigations into the mechanism demonstrate a reduction in the cleavage of procaspase-3, -8, and -9 and the caspase substrate, poly(ADP-ribose)polymerase (PARP). This may be due to Bcl-2, which is normally down-regulated in CD3/CD28-stimulated T cells, but is maintained in the presence of AML TSN. We conclude that AML cells generate an antiapoptotic microenvironment that favors the survival of malignant cells, but also inhibits apoptosis of other normal hemopoietic cells. Reversal of these immunosuppressive effects and restoration of normal immune responses in patients with AML would improve the success of immunotherapy protocols.

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Proapoptotic activity of ITM2Bs, a BH3-only protein induced upon IL-2-deprivation which interacts with Bcl-2

Cited by 38 publications

References 30 publications

Forerunner genes contiguous to RB1 contribute to the development of in situ neoplasia

Forerunner genes contiguous to RB1 contribute to the development of in situ neoplasia

All-trans retinoic acid treatment of Wilms tumor cells reverses expression of genes associated with high risk and relapse in vivo

Antiapoptotic Microenvironment of Acute Myeloid Leukemia

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