Gene interactions and pathways from curated databases and text-mining
Cancer Res 2009, PMID: 19843849

Oncogenic KRAS and BRAF differentially regulate hypoxia-inducible factor-1alpha and -2alpha in colon cancer.

Kikuchi, Hirotoshi; Pino, Maria S; Zeng, Min; Shirasawa, Senji; Chung, Daniel C

KRAS and BRAF mutations are frequently observed in human colon cancers. These mutations occur in a mutually exclusive manner, and each is associated with distinctive biological features. We showed previously that K-ras can interact with hypoxia to activate multiple signaling pathways. Many hypoxic responses are mediated by hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha, and we sought to define the roles of mutant KRAS and BRAF in the induction of HIF-1alpha and HIF-2alpha in colon cancer cells. Ectopic expression of mutant K-ras in Caco2 cells enhanced the hypoxic induction of only HIF-1alpha, whereas mutant BRAF enhanced both HIF-1alpha and HIF-2alpha. Knockout or knockdown of mutant KRAS in DLD-1 and HCT116 cells impaired the hypoxic induction of only HIF-1alpha. HIF-1alpha mRNA levels were comparable in cells with and without a KRAS mutation. However, the rate of HIF-1alpha protein synthesis was higher in cells with a KRAS mutation, and this was suppressed by the phosphoinositide 3-kinase inhibitor LY294002. In contrast, knockdown of mutant BRAF in HT29 cells suppressed both HIF-1alpha and HIF-2alpha. Although BRAF regulated mRNA levels of both HIF-1alpha and HIF-2alpha, knockdown of BRAF or treatment with the MEK inhibitor PD98059 impaired the translation of only HIF-2alpha. Our data reveal that oncogenic KRAS and BRAF mutations differentially regulate the hypoxic induction of HIF-1alpha and HIF-2alpha in colon cancer, and this may potentially contribute to the phenotypic differences of KRAS and BRAF mutations in colon tumors.

Diseases/Pathways annotated by Medline MESH: Anoxia, Colonic Neoplasms
Document information provided by NCBI PubMed

Text Mining Data

HIF-2alpha ⊣ BRAF: " Many hypoxic responses are mediated by hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha, and we sought to define the roles of mutant KRAS and BRAF in the induction of HIF-1alpha and HIF-2alpha in colon cancer cells "

HIF-2alpha ⊣ KRAS: " Many hypoxic responses are mediated by hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha, and we sought to define the roles of mutant KRAS and BRAF in the induction of HIF-1alpha and HIF-2alpha in colon cancer cells "

HIF-1alpha ⊣ BRAF: " Many hypoxic responses are mediated by hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha, and we sought to define the roles of mutant KRAS and BRAF in the induction of HIF-1alpha and HIF-2alpha in colon cancer cells "

HIF-1alpha ⊣ KRAS: " Many hypoxic responses are mediated by hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha, and we sought to define the roles of mutant KRAS and BRAF in the induction of HIF-1alpha and HIF-2alpha in colon cancer cells "

HIF-2alpha → BRAF: " Ectopic expression of mutant K-ras in Caco2 cells enhanced the hypoxic induction of only HIF-1alpha, whereas mutant BRAF enhanced both HIF-1alpha and HIF-2alpha "

HIF-1alpha → BRAF: " Ectopic expression of mutant K-ras in Caco2 cells enhanced the hypoxic induction of only HIF-1alpha, whereas mutant BRAF enhanced both HIF-1alpha and HIF-2alpha "

HIF-1alpha → HIF-2alpha: " Ectopic expression of mutant K-ras in Caco2 cells enhanced the hypoxic induction of only HIF-1alpha , whereas mutant BRAF enhanced both HIF-1alpha and HIF-2alpha "

HIF-1alpha → K-ras: " Ectopic expression of mutant K-ras in Caco2 cells enhanced the hypoxic induction of only HIF-1alpha , whereas mutant BRAF enhanced both HIF-1alpha and HIF-2alpha "

HIF-2alpha → BRAF: " Although BRAF regulated mRNA levels of both HIF-1alpha and HIF-2alpha , knockdown of BRAF or treatment with the MEK inhibitor PD98059 impaired the translation of only HIF-2alpha "

HIF-1alpha → BRAF: " Although BRAF regulated mRNA levels of both HIF-1alpha and HIF-2alpha, knockdown of BRAF or treatment with the MEK inhibitor PD98059 impaired the translation of only HIF-2alpha "

HIF-2alpha → KRAS: " Our data reveal that oncogenic KRAS and BRAF mutations differentially regulate the hypoxic induction of HIF-1alpha and HIF-2alpha in colon cancer, and this may potentially contribute to the phenotypic differences of KRAS and BRAF mutations in colon tumors "

HIF-1alpha → KRAS: " Our data reveal that oncogenic KRAS and BRAF mutations differentially regulate the hypoxic induction of HIF-1alpha and HIF-2alpha in colon cancer, and this may potentially contribute to the phenotypic differences of KRAS and BRAF mutations in colon tumors "

Manually curated Databases

No curated data.