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NORMAL AND ONCOGENIC FUNCTIONS OF BCL10

BCL10 的正常功能和致癌功能

基本信息

批准号：
6757983
负责人：
STEPHAN W MORRIS
金额：
$ 36.65万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-07-01 至 2006-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6757983
关键词：
alleles apoptosis chromosome translocation complementary DNA cysteine endopeptidases gene mutation genetic transcription genetically modified animals laboratory mouse neoplasm /cancer genetics nonHodgkin&apos s lymphoma nuclear factor kappa beta oncoproteins phosphoproteins phosphorylation tumor suppressor proteins yeast two hybrid system

项目摘要

DESCRIPTION: (adapted from the investigator's abstract) The t(1;14)(p22;q32) is a recurrent chromosomal rearrangement specific to the mucosa-associated lymphoid tissue (MALT) lymphomas that results in dysregulation of BCL10, an N-terminal caspase recruitment domain (CARD)-containing apoptosis signaling protein that normally promotes cell death and activates NF-kappaB. Although the mechanisms by which BCL10 induces death and NF-kappaB activity are poorly understood, proapoptosis by the protein appears due in part to binding and activation of procaspase-9 by the Ser/Thr-rich BCL10 C-terminus, which can undergo phosphorylation. In addition to being overexpressed, BCL10 cDNAs from t(1;14)-positive MALT tumors contain a variety of mutations, most resulting in truncations either in or C-termnal to the CARD. BCL10 CARD-truncation mutants are unable to induce death or activate NF-kappaB, while mutants with C-terminal truncations retain NF-kappaB activation but do not induce apoptosis. Because BCL10 promotes apoptosis, it may normally perform a tumor suppressor function. Loss of BCL10 proapoptosis through mutation should confer a survival advantage to cells, and constitutive NF-kappaB activation should provide both antiapoptotic and proliferative signals via its transcriptional targets. The relative importance of these events in tumorigenesis, or whether BCL10 mutants possess additional oncogenic properties, remain unknown. Aim 1a of this proposal seeks to improve understanding of the role of BCL10 in oncogenesis by elucidating its normal function in cell death regulation, using Bc110-null cells to identify the apoptotic pathways that require BCL10 activity and assessing the tumor suppressor capabilities of the protein in vivo. BCL10-interacting proteins and the functional effects of BCL10 C-terminal phosphorylation will be investigated in Aim 1b to further define the mechanisms that govern BCL10 cell death control. The transformation-enhancing properties of various BCL10 mutations will be assessed in Aim 2a, which asks whether biallelic inactivation of BCL10 is required for promotion of oncogenesis, and whether transdominant-inhibitory or transforming gain-of-function monoallelic mutations also contribute to tumor development. Finally, in Aim 2b, the effects of normal BCL10 or selected mutants on lymphoid development and transformation will be assessed in transgenic mice models to ensure the biologic relevance of observations made in previous Aims. Taken together, these studies should clarify the mechanisms by which BCL10 regulates apoptosis and the manner in which BCL10 mutations alter death regulation to promote oncogenesis.

描述：（改编自研究者的摘要）t(1;14)（p22;q32）是

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Phospholipase Cgamma2 provides survival signals via Bcl2 and A1 in different subpopulations of B cells.

磷脂酶 Cgamma2 通过 Bcl2 和 A1 在不同的 B 细胞亚群中提供生存信号。

DOI：
10.1074/jbc.m307318200
发表时间：
2003
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Wen,Renren;Chen,Yuhong;Xue,Liquan;Schuman,James;Yang,Shoua;Morris,StephanW;Wang,Demin
通讯作者：
Wang,Demin

T cell receptor-mediated activation of CD4+CD44hi T cells bypasses Bcl10: an implication of differential NF-kappaB dependence of naïve and memory T cells during T cell receptor-mediated responses.

T 细胞受体介导的 CD4 CD44hi T 细胞激活绕过 Bcl10：T 细胞受体介导的反应期间幼稚 T 细胞和记忆 T 细胞的差异 NF-κB 依赖性的暗示。

DOI：
10.1074/jbc.m802344200
发表时间：
2008
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Zeng,Hu;Chen,Yuhong;Yu,Mei;Xue,Liquan;Gao,Xiang;Morris,StephanW;Wang,Demin;Wen,Renren
通讯作者：
Wen,Renren

RBM15 and MKL1 mutational screening in megakaryoblastic leukemia cell lines and clinical samples.

巨核细胞白血病细胞系和临床样本中的 RBM15 和 MKL1 突变筛查。