title: Overexpression of TRIB2 in human lung cancers contributes to tumorigenesis through downregulation of C/EBPα.
abstract: Lung cancer is the most common cause of cancer-related mortality worldwide. Here, we report elevated expression of tribbles homolog 2 (TRIB2) in primary human lung tumors and in non-small cell lung cancer cells that express low levels of differentiation-inducing transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα). In approximately 10-20% of cases, elevated TRIB2 expression resulted from gene amplification. TRIB2 knockdown was found to inhibit cell proliferation and in vivo tumor growth. In addition, TRIB2 knockdown led to morphological changes similar to C/EBPα overexpression and correlated with increased expression and activity of C/EBPα. TRIB2-mediated regulation of C/EBPα was found to occur through the association of TRIB2 with the E3 ligase TRIM21. Together, these data identify TRIB2 as a potential driver of lung tumorigenesis through a mechanism that involves downregulation of C/EBPα.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA. bgrandinetti@gnf.org
authors.forename: K B
authors.initials: KB
authors.lastname: Grandinetti
authors.forename: T A
authors.initials: TA
authors.lastname: Stevens
authors.forename: S
authors.initials: S
authors.lastname: Ha
authors.forename: R J
authors.initials: RJ
authors.lastname: Salamone
authors.forename: J R
authors.initials: JR
authors.lastname: Walker
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Agarwalla
authors.forename: D G
authors.initials: DG
authors.lastname: Tenen
authors.forename: E C
authors.initials: EC
authors.lastname: Peters
authors.forename: V A
authors.initials: VA
authors.lastname: Reddy
mesh_terms: D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics; D012261:Ribonucleoproteins / Q000378:metabolism; D000099207:SS-A Antigen
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D012261:Ribonucleoproteins; D000099207:SS-A Antigen; C489044:TRIB2 protein, human