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Wild-type H- and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response.

ABSTRACT: Mutations in KRAS are prevalent in human cancers and universally predictive of resistance to anticancer therapeutics. Although it is widely accepted that acquisition of an activating mutation endows RAS genes with functional autonomy, recent studies suggest that the wild-type forms of Ras may contribute to mutant Ras-driven tumorigenesis. Here, we show that downregulation of wild-type H-Ras or N-Ras in mutant K-Ras cancer cells leads to hyperactivation of the Erk/p90RSK and PI3K/Akt pathways and, consequently, the phosphorylation of Chk1 at an inhibitory site, Ser 280. The resulting inhibition of ATR/Chk1 signaling abrogates the activation of the G2 DNA damage checkpoint and confers specific sensitization of mutant K-Ras cancer cells to DNA damage chemotherapeutic agents in vitro and in vivo.

SUBMITTER: Grabocka E

PROVIDER: S-EPMC4063560 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Wild-type H- and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response.

Grabocka Elda E Pylayeva-Gupta Yuliya Y Jones Mathew J K MJ Lubkov Veronica V Yemanaberhan Eyoel E Taylor Laura L Jeng Hao Hsuan HH Bar-Sagi Dafna D

Cancer cell 20140201 2

Mutations in KRAS are prevalent in human cancers and universally predictive of resistance to anticancer therapeutics. Although it is widely accepted that acquisition of an activating mutation endows RAS genes with functional autonomy, recent studies suggest that the wild-type forms of Ras may contribute to mutant Ras-driven tumorigenesis. Here, we show that downregulation of wild-type H-Ras or N-Ras in mutant K-Ras cancer cells leads to hyperactivation of the Erk/p90RSK and PI3K/Akt pathways and ...[more]

PMID: 24525237

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Project description:Ras oncogenes (Hras, Kras and Nras) are important drivers of carcinogenesis. However, tumors with Ras mutations often show loss of the corresponding wild-type (WT) allele, suggesting that proto-oncogenic forms of Ras can function as a suppressor of carcinogenesis. In vitro studies also suggest that WT Ras proteins can suppress the tumorigenic properties of alternate mutant Ras family members, but in vivo evidence for these heterologous interactions is lacking. We have investigated the genetic interactions between different combinations of mutant and WT Ras alleles in vivo using carcinogen-induced lung and skin carcinogenesis in mice with targeted deletion of different Ras family members. The major suppressor effect of WT Kras is observed only in mutant Kras-driven lung carcinogenesis, where loss of one Kras allele led to increased tumor number and size. Deletion of one Hras allele dramatically reduced the number of skin papillomas with Hras mutations, consistent with Hras as the major target of mutation in these tumors. However, skin carcinoma numbers were very similar, suggesting that WT Hras functions as a suppressor of progression from papillomas to invasive squamous carcinomas. In the skin, the Kras proto-oncogene functions cooperatively with mutant Hras to promote papilloma development, although the effect is relatively small. In contrast, the Hras proto-oncogene attenuated the activity of mutant Kras in lung carcinogenesis. Interestingly, loss of Nras increased the number of mutant Kras-induced lung tumors, but decreased the number of mutant Hras-induced skin papillomas. These results show that the strongest suppressor effects of WT Ras are only seen in the context of mutation of the cognate Ras protein, and only relatively weak effects are detected on tumor development induced by mutations in alternative family members. The data also underscore the complex and context-dependent nature of interactions between proto-oncogenic and oncogenic forms of different Ras family members during tumor development.

Dataset Information

Wild-type H- and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response.

Publications

Wild-type H- and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response.

Similar Datasets

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