Identification of MARCKS, FLJ11383 and TAF1B as putative novel target genes in colorectal carcinomas with microsatellite instability

Kim, Nam Gyun; Rhee, Hwanseok; Li, Long Shan; Kim, Hyunki; Lee, Jin Sung; Kim, Joo Hang; Nam, Kyu Kim; Kim, Hoguen

doi:10.1038/sj.onc.1205703

Cited by 48 publications

(55 citation statements)

References 23 publications

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“…Genes matching these criteria include the wellknown Target genes, TGFBR2 and BAX, which corroborate the validity of the present analysis, as well as MACS, TAF1B, and NDUFC2, which have never been examined before in the MSI-H adenomas. In colorectal carcinomas, a high frequency of cMS frameshift mutations has previously been reported for these genes (Mori et al, 2001;Kim et al, 2002;Li et al, 2003;Woerner et al, 2003). MACS, the most prominent cellular substrate for protein kinase C, is thought to be involved in cell motility, phagocytosis, membrane trafficking, and mitogenesis (Blackshear 1993;Li et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…MACS, the most prominent cellular substrate for protein kinase C, is thought to be involved in cell motility, phagocytosis, membrane trafficking, and mitogenesis (Blackshear 1993;Li et al, 2001). Kim et al (2002) speculated that the inactivation of MACS is associated with tumorigenesis. The TAF1B protein is known to constitute an essential part of the RNA polymerase I cofactor SL1 (Comai et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Frameshift mutations in the A 10 coding repeat of this gene have been reported to occur in up to 90% of MSI-H colorectal and 70% of MSI-H gastric cancers Myeroff et al, 1995;Parsons et al, 1995). Several studies identified additional cancer relevant genes like IGF2R, MSH3, MSH6, BAX, CASP5, TCF4, RIZ, AIM2, ACVR2, and TAF1B, which contain cMS and are mutated in MSI-H cancers (Malkhosyan et al, 1996;Souza et al, 1996;Akiyama et al, 1997;Rampino et al, 1997;Duval et al, 1999;Schwartz Jr et al, 1999;Mori et al, 2001;Kim et al, 2002). It is also known that different genes with cMS of identical type and length show major differences in frameshift mutation frequencies in MSI-H tumors (Duval and Hamelin 2002;Woerner et al, 2001Woerner et al, , 2003.…”

Section: Introductionmentioning

confidence: 99%

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Microsatellite instability of selective target genes in HNPCC-associated colon adenomas

et al. 2005

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Microsatellite instability (MSI) occurs in most hereditary nonpolyposis colorectal cancers (HNPCC) and less frequently in sporadic tumors as the result of DNA mismatch repair (MMR) deficiency. Instability at coding microsatellites (cMS) in specific target genes causes frameshift mutations and functional inactivation of affected proteins, thereby providing a selective growth advantage to MMR deficient cells. At present, little is known about Selective Target Gene frameshift mutations in preneoplastic lesions. In this study, we examined 30 HNPCC-associated MSI-H colorectal adenomas of different grades of dysplasia for frameshift mutations in 26 cMS-bearing genes, which, according to our previous model, represent Selective Target genes of MSI. About 30% (8/26) of these genes showed a high mutation frequency (X50%) in colorectal adenomas, similar to the frequencies reported for colorectal carcinomas. Mutations in one gene (PTHL3) occurred significantly less frequently in MSI adenomas compared to published mutation rates in MSI carcinomas (36.0 vs 85.7%, P ¼ 0.023). Biallelic inactivation was observed in nine genes, thus emphasizing the functional impact of cMS instability on MSI tumorigenesis. Some genes showed a high frequency of frameshift mutations already at early stages of MSI colorectal tumorigenesis that increased with grade of dysplasia and transition to carcinoma. These include known Target Genes like BAX and TGFBR2, as well as three novel candidates, MACS, NDUFC2, and TAF1B. Overall, we have identified genes of potential relevance for the initiation and progression of MSI tumorigenesis, thus representing promising candidates for novel diagnostic and therapeutic approaches directed towards MMRdeficient tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Microsatellite instability of selective target genes in HNPCC-associated colon adenomas

et al. 2005

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“…4,5,13 DNA preparation and mutation analysis of the two target genes were performed as described previously. All of the PCR products of these genes showed as one band from the normal DNA, whereas monoallelic or biallelic mutations were detected in some MSI-H tumors (Figures 1 and 2).…”

Section: Detection Of Frameshift Mutationmentioning

confidence: 99%

Impaired nonhomologous end-joining in mismatch repair-deficient colon carcinomas

Koh

Kang

et al. 2005

Laboratory Investigation

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Frameshift mutations of coding mononucleotide repeat of the hRAD50 gene and formation of the mutant hMRE11 splicing variant are frequent events in tumors with mismatch repair (MMR) deficiency. Both the hRAD50 and hMRE11 proteins form a heterotrimer with the NBS1, and this heterotrimer is involved in the double strand DNA break repair by homologous recombination and nonhomologous end-joining (NHEJ). In order to clarify the role of hRAD50 and hMRE11 gene alterations in MMR-deficient tumors, we analyzed the expression of the hRAD50 and hMRE11 proteins and we evaluated NHEJ in the seven MMR-deficient and five MMR-proficient colon cancer cell lines. Frameshift mutations of the hRAD50 gene were found in five of seven MMR-deficient cell lines, and this was directly related to the decreased expression of hRAD50 mRNA and protein. The mutant hMRE11 splicing variant was found in all of the seven MMR-deficient cell lines, and this was related to the decreased hMRE11 expression in four of the seven MMR-deficient cell lines. MMR-deficient cell lines with decreased hRAD50 and hMRE11 expressions were more sensitive to c-irradiation, and these cell lines showed an impaired NHEJ. The impairment of NHEJ was induced after knockdown of hRAD50 and hMRE11 through small interference RNA. Our findings suggest that mutations of hRAD50 and hMRE11 genes in MMR-deficient tumors are related to the defects in NHEJ, and this may result in chromosomal changes during the progression of tumor.

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“…Indeed, genes clearly involved in malignant transformation, such as TGFbRII, BAX or IGFRII (Markowitz et al, 1995;Souza et al, 1996;Rampino et al, 1997), can be inactivated due to MSI. A large number of genes containing coding repeats were found to be affected by MSI and the list of potential target genes was further increased by the use of in silico genome-wide screenings (Kim et al, 2002;Mori et al, 2002;Park et al, 2002;Woerner et al, 2003). However, the isolation of the real targets from the crowds of 'bystanders' awaits biological demonstration of their role in cancer development and progression (Boland et al, 1998;Zhang et al, 2001;.…”

Section: Introductionmentioning

confidence: 99%

Mutations of an intronic repeat induce impaired MRE11 expression in primary human cancer with microsatellite instability

et al. 2004

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Frequent mutations of coding nucleotide repeats are thought to contribute significantly to carcinogenesis associated with microsatellite instability (MSI). We have shown that shortening of the poly(T) 11 within the polypyrimidine stretch/accessory splicing signal of human MRE11 leads to the reduced expression and functional impairment of the MRE11/NBS1/RAD50 complex. This mutation was selectively found in mismatch repair (MMR) defective cell lines and potentially identifies MRE11 as a novel target for MSI. Here, we examined 70 microsatellite unstable primary human cancers and we report that MRE11 mutations occur in 83.7 and 50% of the colorectal and endometrial cancers, respectively. In the colorectal cancer series, mutated MRE11 is more frequently associated with advanced age at diagnosis and A/B stages. Biallelic mutations were present in 38.8% of the cases and more frequently associated with lower (G1/G2) grade tumors. Impaired MRE11 expression was prevalent in primary colorectal tumors with larger and biallelic shortening of the poly(T)11. Immunohistochemistry confirmed the impaired MRE11 expression and revealed NBS1-defective expression in MRE11 mutated cancers. Together with the observation that perturbation of the MRE11/NBS1/RAD50 complex predisposes to cancer, our work highlights MRE11 as a new common target in the MMR deficient tumorigenesis and suggests its role in colorectal carcinogenesis

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Identification of MARCKS, FLJ11383 and TAF1B as putative novel target genes in colorectal carcinomas with microsatellite instability

Cited by 48 publications

References 23 publications

Microsatellite instability of selective target genes in HNPCC-associated colon adenomas

Microsatellite instability of selective target genes in HNPCC-associated colon adenomas

Impaired nonhomologous end-joining in mismatch repair-deficient colon carcinomas

Mutations of an intronic repeat induce impaired MRE11 expression in primary human cancer with microsatellite instability

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