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- 저자 : Threadgill (검색결과 2 건)
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Study of epidermal growth factor receptor function using mouse genetics
Lee, Daekee,David Threadgill 이화여자대학교 세포신호전달연구센터 2005 고사리 세포신호전달 심포지움 Vol. No.7
Since the development of transgenic and gene targeting technologies, mouse models have been central to investigating and understanding mammalian gene function. An impressive array of technologies and the completion of the human and mouse genome sequence accelerate our understanding the gene function and their interactions in normal condition as well as in various diseases. Mice heterozygous for the N-ethyl-N-nitrosourea(ENU)-induced Waved-5(Wa5) mutation, isolated in a screen for dominant, visible mutations, exhibit a wavy coat similar to mice homozygous for the recessive Tgfa^(wa1) or Egfr^(wa2) alleles. Wa5 is a new allele of Egfr(Egfr^(Wa5)) containing a mis-sense mutation within the coding region for a highly conserved DFG motif of the tyrosine kinase domain. In vivo analysis of placental development, modification of Apc^(Min) tumorigenesis and levels of EGF-dependent EGFR phosphorylation demonstrates that Egfr^(Wa5) functions as an antimorphic allele, recapitulating many abnormalities associated with reduced EGFR activity. Furthermore, Egfr^(Wa5) enhances Egfr^(wa2) compound or Tgfa^(tm1Dc1) double mutants exposing additional EGFR-dependent phenotypes. In vitro characterization shows that the antimorphic property of Egfr^(Wa5) is caused by a kinase dead receptor acting as a dominant negative. Epiregulin, an epidermal growth factor family member, acts as a local signal mediator and shows dual biological activity, stimulating the proliferation of fibroblasts, hepatocytes, smooth muscle cells, and keratinocytes while inhibiting the growth of several tumor-derived epithelial cell lines. The epiregulin gene(Ereg) is located on mouse chromosome 5 adjacent to three other epidermal growth factor family members, epigen, amphiregulin, and betacellulin. Gene targeting was used to insert a lacZ reporter into the mouse Ereg locus and to ablate its function. Although epiregulin is broadly expressed and regulated both spatially and temporally, Ereg null mice show no overt developmental defects, reproductive abnormalities, or altered liver regeneration. Additionally, in contrast to previous hypotheses, Ereg deficiency does not alter intestinal cancer susceptibility, as assayed in thy Apc^(Min) model, despite showing robust expression in developing tumors. However, Ereg null mice are highly susceptible to cancer-predisposing intestinal damage caused by oral administration of dextran sulfate sodium.
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Lee, Daekee,Yu, Ming,Lee, Eunjung,Kim, Hyunok,Yang, Yanan,Kim, Kyoungmi,Pannicia, Christina,Kurie, Jonathan M.,Threadgill, David W. American Society for Clinical Investigation 2009 The Journal of clinical investigation Vol.119 No.9
<P>Pharmacologic blockade of EGFR or the closely related receptor ERBB2 has modest efficacy against colorectal cancers in the clinic. Although the upregulation of ERBB3, a pseudo-kinase member of the EGFR/ERBB family, is known to contribute to EGFR inhibitor resistance in other cancers, its functions in normal and malignant intestinal epithelium have not been defined. We have shown here that the intestinal epithelium of mice with intestine-specific genetic ablation of Erbb3 exhibits no cytological abnormalities but does exhibit loss of expression of ERBB4 and sensitivity to intestinal damage. By contrast, intestine-specific Erbb3 ablation resulted in almost complete absence of intestinal tumors in the ApcMin mouse model of colon cancer. Unlike nontransformed epithelium lacking ERBB3, intestinal tumors lacking ERBB3 had reduced PI3K/AKT signaling, which led to attenuation of tumorigenesis via a tumor-specific increase in caspase-3-mediated apoptosis. Consistent with the mouse data, which suggest that ERBB3-ERBB4 heterodimers contribute to colon cancer survival, experimentally induced loss of ERBB3 in a KRAS mutant human colon cancer cell line was associated with loss of ERBB4 expression, and siRNA knockdown of either ERBB3 or ERBB4 resulted in elevated levels of apoptosis. These results indicate that the ERBB3 pseudo-kinase has essential roles in supporting intestinal tumorigenesis and suggest that ERBB3 may be a promising target for the treatment of colorectal cancers.</P>
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