Ligand stimulation of IGF-IR causes its dimerization and phosphorylation, and subsequent activation of downstream signaling systems. IGF-IR belongs to the insulin receptor family whose members exhibit a common structural characteristic in the form of an amino acid motif (Y XXXYY) within the activation loop of their respective kinase domains. The type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase is a homodimeric protein that is composed of 2 extracellular α and 2 transmembranous β subunits connected by disulfide bonds. These findings could be exploited to devise new strategies to eradicate this lymphoma. Our results provide novel evidence that the aberrant decreases in Ik-1 and MZF1 contribute significantly to the pathogenesis of NPM-ALK + T-cell lymphoma through the upregulation of IGF-IR expression. In addition, overexpression of Ik-1 and MZF1 decreased the viability, proliferation, migration, and anchorage-independent colony formation of the lymphoma cells. This decrease was associated with downregulation of pIGF-IR, and the phosphorylation of its interacting proteins IRS-1, AKT, and NPM-ALK. Forced expression of Ik-1 or MZF1 in the lymphoma cells decreased IGF-IR mRNA and protein. Furthermore, ChIP assay showed that these transcription factors bind specific sites located within the IGF-IR gene promoter. A luciferase assay supported that Ik-1 and MZF1 suppress IGF-IR gene promoter. Screening studies showed substantially lower levels of the transcription factors Ikaros isoform 1 (Ik-1) and myeloid zinc finger 1 (MZF1) in NPM-ALK + T-cell lymphoma cell lines and primary tumor tissues from patients than in human T lymphocytes. We hypothesized that upregulation of IGF-IR could be attributed to previously unrecognized defects that inherently exist in the transcriptional machinery in NPM-ALK + T-cell lymphoma. The mechanisms underlying increased expression of IGF-IR in this lymphoma are not known. NPM-ALK + T-cell lymphoma exhibits much higher levels of IGF-IR than normal human T lymphocytes. The type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase promotes the survival of an aggressive subtype of T-cell lymphoma by interacting with nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) oncogenic protein.
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