Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia

被引：170

作者：

Hodson, Daniel J. ^{[1
]}

Janas, Michelle L. ^{[1
]}

Galloway, Alison ^{[1
]}

Bell, Sarah E. ^{[1
]}

Andrews, Simon ^{[2
]}

Li, Cheuk M. ^{[1
]}

Pannell, Richard ^{[3
]}

Siebel, Christian W. ^{[4
]}

MacDonald, H. Robson ^{[5
]}

De Keersmaecker, Kim ^{[6
]}

Ferrando, Adolfo A. ^{[6
,7
,8
]}

Grutz, Gerald ^{[9
,10
]}

Turner, Martin ^{[1
]}

机构：

[1] Babraham Inst, Lab Lymphocyte Signalling & Dev, Cambridge, England

[2] Babraham Inst, Bioinformat Grp, Cambridge, England

[3] MRC, Mol Biol Lab, Cambridge CB2 2QH, England

[4] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA

[5] Univ Lausanne, Ludwig Inst Canc Res, Lausanne Branch, CH-1066 Epalinges, Switzerland

[6] Columbia Univ, Med Ctr, Inst Canc Genet, New York, NY USA

[7] Columbia Univ, Dept Pathol, Med Ctr, New York, NY USA

[8] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10027 USA

[9] Charite, Inst Med Immunol, D-13353 Berlin, Germany

[10] GKSS, Ctr Biomat Dev, Polymer Res Inst, Teltow, Germany

来源：

NATURE IMMUNOLOGY | 2010年 / 11卷 / 08期

基金：

英国医学研究理事会; 英国生物技术与生命科学研究理事会; 美国国家卫生研究院;

关键词：

AU-RICH ELEMENT; PRE-TCR SIGNALS; THYMOCYTE DIFFERENTIATION; CELL DEVELOPMENT; BETA-SELECTION; MESSENGER-RNAS; KINASE-B; NOTCH; TRISTETRAPROLIN; MICE;

D O I：

10.1038/ni.1901

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

ZFP36L1 and ZFP36L2 are RNA-binding proteins (RBPs) that interact with AU-rich elements in the 3' untranslated region of mRNA, which leads to mRNA degradation and translational repression. Here we show that mice that lacked ZFP36L1 and ZFP36L2 during thymopoiesis developed a T cell acute lymphoblastic leukemia (T-ALL) dependent on the oncogenic transcription factor Notch1. Before the onset of T-ALL, thymic development was perturbed, with accumulation of cells that had passed through the beta-selection checkpoint without first expressing the T cell antigen receptor beta-chain (TCR beta). Notch1 expression was higher in untransformed thymocytes in the absence of ZFP36L1 and ZFP36L2. Both RBPs interacted with evolutionarily conserved AU-rich elements in the 3' untranslated region of Notch1 and suppressed its expression. Our data establish a role for ZFP36L1 and ZFP36L2 during thymocyte development and in the prevention of malignant transformation.

引用

页码：717 / U84

页数：9

共 49 条

[1] Notch signaling in leukemia [J].

Aster, Jon C. ;

Pear, Warren S. ;

Blacklow, Stephen C. .

ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE, 2008, 3 :587-613

[2] Involvement of Tis11b, an AU-rich binding protein, in induction of apoptosis by rituximab in B cell chronic lymphocytic leukemia cells [J].

Baou, M. ;

Jewell, A. ;

Muthurania, A. ;

Wickremasinghe, R. G. ;

Yong, K. L. ;

Carr, R. ;

Marsh, P. ;

Murphy, J. J. .

LEUKEMIA, 2009, 23 (05) :986-989

[3] The RNA binding protein Zfp36l1 is required for normal vascularisation and post-transcriptionally regulates VEGF expressiono [J].

Bell, Sarah E. ;

Sanchez, Maria Jose ;

Spasic-Boskovic, Olivera ;

Santalucia, Tomas ;

Gambardella, Laure ;

Burton, Graham J. ;

Murphy, John J. ;

Norton, John D. ;

Clark, Andrew R. ;

Turner, Martin .

DEVELOPMENTAL DYNAMICS, 2006, 235 (11) :3144-3155

[4] mRNA stability and cancer: an emerging link? [J].

Benjamin, Don ;

Moroni, Christoph .

EXPERT OPINION ON BIOLOGICAL THERAPY, 2007, 7 (10) :1515-1529

[5] BRF1 protein turnover and mRNA decay activity are regulated by protein kinase B at the same phosphorylation sites [J].

Benjamin, Don ;

Schmidlin, Martin ;

Min, Lu ;

Gross, Brigitte ;

Moroni, Christoph .

MOLECULAR AND CELLULAR BIOLOGY, 2006, 26 (24) :9497-9507

[6] Characteristics of the interaction of a synthetic human tristetraprolin tandem zinc finger peptide with AU-rich element-containing RNA substrates [J].

Blackshear, PJ ;

Lai, WS ;

Kennington, EA ;

Brewer, G ;

Wilson, GM ;

Guan, XJ ;

Zhou, P .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (22) :19947-19955

[7] The mRNA-Destabilizing Protein Tristetraprolin Is Suppressed in Many Cancers, Altering Tumorigenic Phenotypes and Patient Prognosis [J].

Brennan, Sarah E. ;

Kuwano, Yuki ;

Alkharouf, Nadim ;

Blackshear, Perry J. ;

Gorospe, Myriam ;

Wilson, Gerald M. .

CANCER RESEARCH, 2009, 69 (12) :5168-5176

[8] Notch1-dependent lymphomagenesis is assisted by but does not essentially require pre-TCR signaling [J].

Campese, Antonio F. ;

Garbe, Annette I. ;

Zhang, Fangrong ;

Grassi, Fabio ;

Screpanti, Isabella ;

von Boehmer, Harald .

BLOOD, 2006, 108 (01) :305-310

[9] Feedback inhibition of macrophage tumor necrosis factor-α production by tristetraprolin [J].

Carballo, E ;

Lai, WS ;

Blackshear, PJ .

SCIENCE, 1998, 281 (5379) :1001-1005

[10] Notch promotes survival of pre-T cells at the β-selection checkpoint by regulating cellular metabolism [J].

Ciofani, M ;

Zúñiga-Pflücker, JC .

NATURE IMMUNOLOGY, 2005, 6 (09) :881-888

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