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Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K-ras oncogene in vivo 总被引:3,自引:0,他引:3 下载免费PDF全文
Sansom OJ Meniel V Wilkins JA Cole AM Oien KA Marsh V Jamieson TJ Guerra C Ashton GH Barbacid M Clarke AR 《Proceedings of the National Academy of Sciences of the United States of America》2006,103(38):14122-14127
Oncogenic mutations in the K-ras gene occur in approximately 50% of human colorectal cancers. However, the precise role that K-ras oncogenes play in tumor formation is still unclear. To address this issue, we have conditionally expressed an oncogenic K-ras(V12) allele in the small intestine of adult mice either alone or in the context of Apc deficiency. We found that expression of K-ras(V12) does not affect normal intestinal homeostasis or the immediate phenotypes associated with Apc deficiency. Mechanistically we failed to find activation of the Raf/MEK/ERK pathway, which may be a consequence of the up-regulation of a number of negative feedback loops. However, K-ras(V12) expression accelerates intestinal tumorigenesis and confers invasive properties after Apc loss over the long term. In renal epithelium, expression of the oncogenic K-ras(V12) allele in the absence of Apc induces the rapid development of renal carcinoma. These tumors, unlike those of intestinal origin, display activation of the Raf/MEK/ERK and Akt signaling pathways. Taken together, these data indicate that normal intestinal and kidney epithelium are resistant to malignant transformation by an endogenous K-ras oncogene. However, activation of K-ras(V12) after Apc loss results in increased tumorigenesis with distinct kinetics. Whereas the effect of K-ras oncogenes in the intestine can been observed only after long latencies, they result in rapid carcinogenesis in the kidney epithelium. These data imply a window of opportunity for anti-K-ras therapies after tumor initiation in preventing tumor growth and invasion. 相似文献
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Humans have antibodies capable of recognizing oncoviral glycoproteins: demonstration that these antibodies are formed in response to cellular modification of glycoproteins rather than as consequence of exposure to virus. 总被引:4,自引:3,他引:4 下载免费PDF全文
M Barbacid D Bolognesi S A Aaronson 《Proceedings of the National Academy of Sciences of the United States of America》1980,77(3):1617-1621
There is controversy in the literature concerning the presence in humans of antibodies directed against the envelope glycoproteins of known oncoviruses. In the present report, we show that antibodies capable of precipitating a wide variety of oncoviral glycoproteins can be demonstrated under certain assay conditions. Substances as diverse as normal components of serum, extracts of bacteria, and even nonprotein molecules such as glycogen also shared the oncoviral glycoprotein determinants recognized by normal human sera. It was found that immunoprecipitation of a given viral glycoprotein by human sera was entirely dependent upon the cell in which the virus was grown. Human sera specifically did not recognize glycoproteins purified from oncoviruses grown in human or higher primate cells. These findings not only demonstrate that the antibodies were directed against cellular rather than the virus-coded antigenic determinants but also exclude the possibility that this immune response was elicited as a consequence of oncovirus exposure. 相似文献
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Wild mouse RNA tumor viruses. A nongenetically transmitted virus group closely related to exogenous leukemia viruses of laboratory mouse strains 总被引:8,自引:0,他引:8 下载免费PDF全文
Type-C RNA viruses isolated from wild mice are causative of naturally occurring neoplasia and neurologic diseases. Biochemical and immunologic characterization of this virus group revealed that amphotropic viruses isolated from wild mice trapped in separate geographical areas are indistinguishable, whereas amphotropic and ecotropic viruses naturally infecting the same animal are env gene variants. Molecular hybridization studies established that neither host range variant is endogenous to the Mus musculus genome, although each demonstrates partial nucleotide sequence homology. Wild mouse type-C viruses exhibited much closer molecular and antigenic relatedness to the exogenous virus subgroup (Friend-, Moloney-, and Rauscher-MuLV) than to prototype endogenous viruses isolated from laboratory mouse strains. The evidence indicates that exogenous mouse type-C viruses have been maintained in nature over a long period of evolution as a separate virus group, causative of tumors in mice by a mechanism solely involving their transmission as infectious agents. 相似文献
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Identification and biochemical characterization of p70TRK, product of the human TRK oncogene. 总被引:6,自引:2,他引:6 下载免费PDF全文
G Mitra D Martin-Zanca M Barbacid 《Proceedings of the National Academy of Sciences of the United States of America》1987,84(19):6707-6711
TRK is a human transforming gene generated in a colon carcinoma by a somatic rearrangement that fused a nonmuscle tropomyosin gene to sequences that shared extensive homology with members of the tyrosine-protein kinase supergene family. These sequences are likely to be derived from a transmembrane receptor gene whose putative ligand binding domain has been replaced by tropomyosin. In the present studies, we have expressed the entire coding sequences of the TRK oncogene as well as its protein kinase-related carboxyl-terminal domain in Escherichia coli. Antisera raised against these bacteria-synthesized TRK polypeptides has allowed us to identify the gene product of the TRK oncogene as a 70-kDa protein. Immunoprecipitates containing p70TRK have an associated protein kinase activity specific for tyrosine residues. Moreover, p70TRK is phosphorylated in vivo in serine (75%), threonine (20%), and tyrosine (5%) residues. Finally, immunofluorescence and cellular fractionation studies indicate that p70TRK is preferentially located in the cytoplasmic fraction. 相似文献
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Oncogenes and human cancer: cause or consequence? 总被引:13,自引:0,他引:13
M Barbacid 《Carcinogenesis》1986,7(7):1037-1042
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The transformation-specific proteins of avian (Fujinami and PRC-II) and feline (Synder--Theilen and Gardner--Arnstein) sarcoma viruses are immunologically related 总被引:14,自引:0,他引:14
The detection of protein kinase activity associated with transformation-specific gene products of Rous sarcoma virus (RSV), Abelson murine leukemia virus (Ab-MuLV), the Snyder-Theilen (ST), and Gardner-Arnstein (GA) strains of feline sarcoma virus (FeSV) and the recently characterized Fujinami (FSV) and PRCII avian sarcoma viruses suggests that these viruses may induce oncogenic transformation by similar mechanisms. In spite of their similar enzymatic properties, the transformation-specific proteins of RSV or Ab-MuLV were not found to share common antigenic determinants with those of the ST or the GA strains of FeSV. These results suggest that vertebrates contain multiple unrelated genes that code for proteins with associated tyrosine-specific protein kinase activity and oncogenic properties when incorporated into the genome of a retrovirus. In contrast, the transformation-specific proteins of ST and GA-FeSV were shown to be immunologically related to those of the FSV and PRCII avian sarcoma viruses. The antigenic determinants shared by these viral proteins have been mapped within their respective sarcoma virus-specific regions, suggesting that the cellular insertions present in these avian and feline sarcoma viruses are related. These observations indicate that potentially oncogenic sequences have been conserved during the evolution of feline and avian genomes and have been independently acquired by two sets of sarcoma viruses. 相似文献