Trib1 links the MEK1/ERK pathway in myeloid leukemogenesis.
Trib1 is a myeloid oncogene that cooperates with Hoxa9 and Meis1. Although the MAPK pathway and C/EBP transcription factors are known to interact with Trib proteins, the mechanisms by which Trib1 contributes to myeloid leukemogenesis remains to be clarified. Here we report that interaction between Trib1 and MEK1 is required for Trib1-induced leukemogenesis. The C-terminal ILLHPWF motif that is well conserved among Trib family proteins is required for MEK1 binding, enhancement of ERK phosphorylation, enhanced self-renewal activity of bone marrow cells and leukemogenic activity by Trib1. The motif is also important for Trib1-induced C/EBPα degradation though interaction between Trib1 and C/EBPα is not necessary. Inhibition of ERK phosphorylation suppressed Trib1-induced C/EBPα degradation, indicating an important role for Trib1/MEK1 interaction. These results suggest that Trib1 may be a key mediator between the RTK-MAPK pathway and the C/EBP transcription factor in myeloid leukemogenesis.
Yokoyama
Takashi
T
Division of Carcinogenesis, The Cancer Institute, Tokyo, Japan.
Kanno
Yohei
Y
Yamazaki
Yukari
Y
Takahara
Tomoko
T
Miyata
Satoshi
S
Nakamura
Takuro
T
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009857:Oncogenes; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000037:antagonists & inhibitors
D022763:CCAAT-Enhancer-Binding Protein-alpha; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C493170:TRIB1 protein, human; C097899:homeobox protein HOXA9; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human