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Inhibition of muscle-specific gene expression by Id3: requirement of the C-terminal region of the protein for stable expression and function. 总被引:1,自引:0,他引:1
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We have examined the role of an Id-like protein, Id3 (also known as HLH462), in the regulation of muscle-specific gene expression. Id proteins are believed to block expression of muscle-specific genes by preventing the dimerization between ubiquitous bHLH proteins (E proteins) and myogenic bHLH proteins such as MyoD. Consistent with its putative role as an inhibitor of differentiation, Id3 mRNA was detected in proliferating skeletal muscle cells, was further induced by basic fibroblast growth factor (bFGF) and was down-regulated in differentiated muscle cultures. Overexpression of Id3 efficiently inhibited the MyoD-mediated activation of the muscle-specific creatine kinase (MCK) reporter gene. Deletion analysis indicated that the C-terminal 15 amino acids of Id3 are critical for the full inhibitory activity while deleting up to 42 residues from the C-terminus of the related protein, Id2, did not affect its ability to inhibit the MCK reporter gene. Chimeric protein containing the N-terminal region of Id3 and the C-terminus of Id2 was also non-functional in transfected cells. In contrast, wild-type Id3, the C-terminal mutants, and the Id3/Id2 chimera could all interact with the E-protein E47in vitro. Additional studies indicated that truncation of the Id3 C-terminus might have adversely affected the expression level of the mutant proteins but the Id3/Id2 chimera was stably expressed. Taken together, our results revealed a more complex requirement for the expression and proper function of the Id family proteins than was hitherto expected. 相似文献
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Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. 总被引:73,自引:0,他引:73
D Lyden K Hattori S Dias C Costa P Blaikie L Butros A Chadburn B Heissig W Marks L Witte Y Wu D Hicklin Z Zhu N R Hackett R G Crystal M A Moore K A Hajjar K Manova R Benezra S Rafii 《Nature medicine》2001,7(11):1194-1201
The role of bone marrow (BM)-derived precursor cells in tumor angiogenesis is not known. We demonstrate here that tumor angiogenesis is associated with recruitment of hematopoietic and circulating endothelial precursor cells (CEPs). We used the angiogenic defective, tumor resistant Id-mutant mice to show that transplantation of wild-type BM or vascular endothelial growth factor (VEGF)-mobilized stem cells restore tumor angiogenesis and growth. We detected donor-derived CEPs throughout the neovessels of tumors and Matrigel-plugs in an Id1+/-Id3-/- host, which were associated with VEGF-receptor-1-positive (VEGFR1+) myeloid cells. The angiogenic defect in Id-mutant mice was due to impaired VEGF-driven mobilization of VEGFR2+ CEPs and impaired proliferation and incorporation of VEGFR1+ cells. Although targeting of either VEGFR1 or VEGFR2 alone partially blocks the growth of tumors, inhibition of both VEGFR1 and VEGFR2 was necessary to completely ablate tumor growth. These data demonstrate that recruitment of VEGF-responsive BM-derived precursors is necessary and sufficient for tumor angiogenesis and suggest new clinical strategies to block tumor growth. 相似文献
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Sakurai D Tsuchiya N Yamaguchi A Okaji Y Tsuno NH Kobata T Takahashi K Tokunaga K 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(9):5801-5809
Angiogenesis plays a pivotal role in the aggressive proliferation of synovial cells in rheumatoid arthritis. We have previously reported the overexpression of inhibitor of DNA binding/differentiation (Id) in the endothelial cells within the synovial tissues of rheumatoid arthritis. In this study, we investigated the role of Id in inflammation and angiogenesis in an in vitro model using HUVECs. Vascular endothelial growth factor (VEGF) and TGFbeta induced the expression of Id1 and Id3 in HUVECs. Forced expression of Id induced proliferative activity in HUVECs accompanied by down-regulation of p16INK4a. Overexpression of Id enhanced expression of ICAM-1 and E-selectin, and induced angiogenic processes such as transmigration, matrix metalloproteinase-2 and -9 expression, and tube formation. In contrast, knockdown of Id1 and Id3 with RNA interference abolished proliferation, activation, and angiogenic processes of HUVECs induced by VEGF. These results indicated that Id plays a crucial role in VEGF-induced signals of endothelial cells by causing activation and potentiation of angiogenic processes. Based on these findings, it was proposed that inhibition of expression and/or function of Id1 and Id3 may potentially be of therapeutic value for conditions associated with pathological angiogenesis. 相似文献
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Specific in vivo association between the bHLH and LIM proteins implicated in human T cell leukemia. 总被引:21,自引:5,他引:21
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I Wadman J Li R O Bash A Forster H Osada T H Rabbitts R Baer 《The EMBO journal》1994,13(20):4831-4839
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