Publication Date:
2011-01-29
Description:
Proper regulation of nuclear factor kappaB (NF-kappaB) transcriptional activity is required for normal lymphocyte function, and deregulated NF-kappaB signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-kappaB-inducing kinase (NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-kappaB signaling, enhanced B cell adhesion, and apoptosis resistance. Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-kappaB pathway in B lymphoproliferative disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124150/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124150/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rosebeck, Shaun -- Madden, Lisa -- Jin, Xiaohong -- Gu, Shufang -- Apel, Ingrid J -- Appert, Alex -- Hamoudi, Rifat A -- Noels, Heidi -- Sagaert, Xavier -- Van Loo, Peter -- Baens, Mathijs -- Du, Ming-Qing -- Lucas, Peter C -- McAllister-Lucas, Linda M -- R01 CA124540/CA/NCI NIH HHS/ -- R01 CA124540-04/CA/NCI NIH HHS/ -- R01 HL082914/HL/NHLBI NIH HHS/ -- R01CA124540/CA/NCI NIH HHS/ -- T32-HD07513/HD/NICHD NIH HHS/ -- T32-HL007622-21A2/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2011 Jan 28;331(6016):468-72. doi: 10.1126/science.1198946.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21273489" target="_blank"〉PubMed〈/a〉
Keywords:
Apoptosis
;
B-Lymphocytes/*metabolism
;
Cell Adhesion
;
Cell Line
;
Cell Line, Tumor
;
Gene Expression Regulation, Neoplastic
;
Humans
;
I-kappa B Kinase/metabolism
;
Lymphoma, B-Cell, Marginal Zone/genetics/*metabolism
;
NF-kappa B/*metabolism
;
NF-kappa B p52 Subunit/metabolism
;
Oncogene Proteins, Fusion/chemistry/genetics/*metabolism
;
Phosphorylation
;
Protein Structure, Tertiary
;
Protein-Serine-Threonine Kinases/genetics/*metabolism
;
Proto-Oncogene Proteins/genetics/metabolism
;
Signal Transduction
;
Substrate Specificity
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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