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 1 a 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA087064-01
Application #
6166033
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mufson, R Allan
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
1
Fiscal Year
2000
Total Cost
$323,449
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Xu, Wu; Xue, Liquan; Sun, Yi et al. (2013) Bcl10 is an essential regulator for A20 gene expression. J Physiol Biochem 69:821-34
Huang, Xiangwei; Yang, Naiheng; Fiore, Vincent F et al. (2012) Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction. Am J Respir Cell Mol Biol 47:340-8
Li, Zhaoyang; Wang, Hongsheng; Xue, Liquan et al. (2009) Emu-BCL10 mice exhibit constitutive activation of both canonical and noncanonical NF-kappaB pathways generating marginal zone (MZ) B-cell expansion as a precursor to splenic MZ lymphoma. Blood 114:4158-68
Hanna, Mary; Liu, Haibo; Amir, Jawaria et al. (2009) Mechanical regulation of the proangiogenic factor CCN1/CYR61 gene requires the combined activities of MRTF-A and CREB-binding protein histone acetyltransferase. J Biol Chem 284:23125-36
Zeng, Hu; Chen, Yuhong; Yu, Mei et al. (2008) T cell receptor-mediated activation of CD4+CD44hi T cells bypasses Bcl10: an implication of differential NF-kappaB dependence of naive and memory T cells during T cell receptor-mediated responses. J Biol Chem 283:24392-9
Hara, Hiromitsu; Ishihara, Chitose; Takeuchi, Arata et al. (2008) Cell type-specific regulation of ITAM-mediated NF-kappaB activation by the adaptors, CARMA1 and CARD9. J Immunol 181:918-30
Wang, Donghai; You, Yun; Lin, Pei-Chun et al. (2007) Bcl10 plays a critical role in NF-kappaB activation induced by G protein-coupled receptors. Proc Natl Acad Sci U S A 104:145-50
Chen, Yuhong; Pappu, Bhanu P; Zeng, Hu et al. (2007) B cell lymphoma 10 is essential for FcepsilonR-mediated degranulation and IL-6 production in mast cells. J Immunol 178:49-57
Hara, Hiromitsu; Ishihara, Chitose; Takeuchi, Arata et al. (2007) The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors. Nat Immunol 8:619-29
Sun, Yi; Boyd, Kelli; Xu, Wu et al. (2006) Acute myeloid leukemia-associated Mkl1 (Mrtf-a) is a key regulator of mammary gland function. Mol Cell Biol 26:5809-26

Showing the most recent 10 out of 17 publications