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Title: Characterization of a novel oncogenic K-ras mutation in colon cancer

Abstract

Activating mutations of RAS are frequently observed in subsets of human cancers, indicating that RAS activation is involved in tumorigenesis. Here, we identified and characterized a novel G to T transversion mutation of the K-ras gene at the third position of codon 19 (TTG) which substituted phenylalanine for leucine in 3 primary colon carcinomas. Biological and biochemical activity was examined using transformed NIH3T3 cells expressing mutant or wild-type K-ras. Transformants harboring the K-ras mutation at codon 19 showed proliferative capacity under serum-starved conditions, less contact inhibition, anchorage-independent growth, tumorigenicity in nude mice and elevation of active Ras-GTP levels. These results indicated that this novel mutation possesses high oncogenic activity.

Authors:
 [1];  [2];  [3];  [2];  [4];  [4]
  1. Molecular Diagnosis and Cancer Prevention Division, Saitama Cancer Center, 818 Komuro Ina, Kitaadachigun, Saitama 362-0806 (Japan) and Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro Ina, Kitaadachigun, Saitama 362-0806 (Japan). E-mail: akagi@cancer-c.pref.saitama.jp
  2. Molecular Diagnosis and Cancer Prevention Division, Saitama Cancer Center, 818 Komuro Ina, Kitaadachigun, Saitama 362-0806 (Japan)
  3. Gastroenterology Division, Saitama Cancer Center, 818 Komuro Ina, Kitaadachigun, Saitama 362-0806 (Japan)
  4. Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro Ina, Kitaadachigun, Saitama 362-0806 (Japan)
Publication Date:
OSTI Identifier:
20857968
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 352; Journal Issue: 3; Other Information: DOI: 10.1016/j.bbrc.2006.11.091; PII: S0006-291X(06)02560-5; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOCHEMISTRY; CARCINOMAS; GENES; INHIBITION; LARGE INTESTINE; LEUCINE; MICE; MUTANTS; MUTATIONS; PHENYLALANINE

Citation Formats

Akagi, Kiwamu, Uchibori, Ryosuke, Yamaguchi, Kensei, Kurosawa, Keiko, Tanaka, Yoichiro, and Kozu, Tomoko. Characterization of a novel oncogenic K-ras mutation in colon cancer. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2006.11.091.
Akagi, Kiwamu, Uchibori, Ryosuke, Yamaguchi, Kensei, Kurosawa, Keiko, Tanaka, Yoichiro, & Kozu, Tomoko. Characterization of a novel oncogenic K-ras mutation in colon cancer. United States. doi:10.1016/j.bbrc.2006.11.091.
Akagi, Kiwamu, Uchibori, Ryosuke, Yamaguchi, Kensei, Kurosawa, Keiko, Tanaka, Yoichiro, and Kozu, Tomoko. Fri . "Characterization of a novel oncogenic K-ras mutation in colon cancer". United States. doi:10.1016/j.bbrc.2006.11.091.
@article{osti_20857968,
title = {Characterization of a novel oncogenic K-ras mutation in colon cancer},
author = {Akagi, Kiwamu and Uchibori, Ryosuke and Yamaguchi, Kensei and Kurosawa, Keiko and Tanaka, Yoichiro and Kozu, Tomoko},
abstractNote = {Activating mutations of RAS are frequently observed in subsets of human cancers, indicating that RAS activation is involved in tumorigenesis. Here, we identified and characterized a novel G to T transversion mutation of the K-ras gene at the third position of codon 19 (TTG) which substituted phenylalanine for leucine in 3 primary colon carcinomas. Biological and biochemical activity was examined using transformed NIH3T3 cells expressing mutant or wild-type K-ras. Transformants harboring the K-ras mutation at codon 19 showed proliferative capacity under serum-starved conditions, less contact inhibition, anchorage-independent growth, tumorigenicity in nude mice and elevation of active Ras-GTP levels. These results indicated that this novel mutation possesses high oncogenic activity.},
doi = {10.1016/j.bbrc.2006.11.091},
journal = {Biochemical and Biophysical Research Communications},
number = 3,
volume = 352,
place = {United States},
year = {Fri Jan 19 00:00:00 EST 2007},
month = {Fri Jan 19 00:00:00 EST 2007}
}
  • Human ESX1 is a 65-kilodalton (kDa) paired-like homeoprotein that is proteolytically processed into N-terminal 45-kDa and C-terminal 20-kDa fragments. The N-terminal ESX1 fragment, which contains the homeodomain, localizes to the nucleus and represses mRNA transcription from the K-ras gene. When we inoculated human colorectal carcinoma HCT116 constitutive expressing N-terminal region of ESX1 (N-ESX1) into nude mice, transfectant cells uniformly showed decreased tumor-forming activity compared with that of the parental cells. Furthermore, pretreatment of HCT116 carcinoma cells with a fusion protein consisting of N-ESX1 and the protein-transduction domain derived from the human immunodeficiency virus type-1 TAT protein gave rise to amore » dramatic reduction in the tumorigenicity of HCT116 cells in nude mice. Our results provide first in vivo evidence for the molecular targeting therapeutic application of the K-ras repressor ESX1, especially TAT-mediated transduction of N-ESX1, in the treatment of human cancers having oncogenic K-ras mutations.« less
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