Biomedical subjects

Carrie R Graveel

Publications and source records attributed to Carrie R Graveel.

3 recordsLinked to original sources

PubMed2005

A mouse model of activating Met mutations.

Tyrosine kinase-activating mutations in Met have been observed in hereditary papillary renal carcinomas (HPRC) and their transforming potential has been examined both in vitro and in tumor xenografts. To study the influence of these mutations in the mouse germline, we generated mice with targeted mutations in the murine met locus. Five mouse lines with mutant Met were created: WT, D1226N, Y1228C, M1248T, and M1248T/L1193V. Unexpectedly, the different mutant Met lines developed unique tumor profiles including carcinomas, sarcomas, and lymphomas. More surprising was that we observed non-random duplication of the mutant met allele in a majority of tumors from the mutant mouse lines. This selective chromosomal amplification has been observed in patients with HPRC. This study illustrates the importance of activating Met mutations in tumorigenesis and indicates that mutations within the kinase domain distinctly affect downstream signaling. Our Met mutant mice will provide a valuable model for testing Met inhibitors on tumors containing activating mutations present in human cancers and for understanding the molecular events critical for Met-mediated tumorigenesis.

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PubMed2003

Identification and characterization of CRG-L2, a new marker for liver tumor development.

Liver cancer is very common worldwide and the rates of hepatocellular carcinoma (HCC) have increased by over 70% in the last 2 decades in the US. Late diagnosis, because of the lack of clinical symptoms, and decreased hepatic function, because of underlying hepatic disease, lead to the extremely high mortality rates associated with HCC. Clearly, the identification of markers that are expressed early in the development of HCC and that are easily detected in high-risk patients would aid in early diagnosis and increased survival. We present the cloning and characterization of a novel gene, CRG-L2 (Cancer related gene-Liver 2), which displays high expression in murine and human hepatocellular carcinomas. Using in situ hybridization, we show that CRG-L2 mRNA levels are increased early during the development of liver tumors in C3H/HeJ mice, and that in normal tissues CRG-L2 mRNA is restricted to the murine testis and human placenta. Its restricted expression in normal tissues and unique early upregulation during tumor development make CRG-L2 an excellent candidate as a new clinical marker of HCC.

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PubMed2002

The identification of E2F1-specific target genes.

The E2F family of transcriptional regulators consists of six different members. Analysis of E2F-regulated promoters by using cultured cells suggests that E2Fs may have redundant functions. However, animal studies have shown that loss of individual E2Fs can have distinct biological consequences. Such seemingly conflicting results could be due to a difference in E2F-mediated regulation in cell culture vs. animals. Alternatively, there may be genes that are specifically regulated by an individual E2F which have not yet been identified. To investigate this possibility further, we have analyzed gene expression in E2F1 nullizygous mice. We found that loss of E2F1 did not cause changes in expression of known E2F target genes, suggesting that perhaps E2F1-specific promoters are distinct from known E2F target promoters. Therefore, we used oligonucleotide microarrays to identify mRNAs whose expression is altered on loss of E2F1. We demonstrate by chromatin immunoprecipitation that several of the promoters that drive expression of the deregulated mRNAs selectively recruit E2F1, but not other E2Fs, and this recruitment is via an element distinct from a consensus E2F binding site. To our knowledge, these are as yet undocumented examples of promoters being occupied in asynchronously growing cells by a single E2F family member. Interestingly, the E2F1-specific target genes that we identified encode proteins having functions quite different from the function of known E2F target genes. Thus, whereas E2F1 may share redundant functions in cell growth control with other E2F family members, it may also play an important biological role distinct from the other E2Fs.

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