Carcinogenesis Advance Access published online on May 5, 2006
Carcinogenesis, doi:10.1093/carcin/bgl063
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1 Grup d'Oncogenesi i Antitumorals, Institut de Recerca, Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain
* To whom correspondence should be addressed. Different mutant amino acids in the Ras proteins lead to distinct transforming capacities and different aggressiveness in human tumors. K-Ras Asp12 (K12D) is more prevalent in benign than in malignant human colorectal tumors, whereas K-Ras Val12 (K12V) associates with more advanced and metastatic carcinomas, higher recurrence and decreased survival. Here, we tested, in a nude mouse xenograft model, whether different human K-Ras oncogenes mutated at codon 12 to Val, Asp or Cys would confer NIH3T3 fibroblasts distinct oncogenic phenotypes. We studied tumor histology and growth, apoptotic and mitotic rates, activation of signal transduction pathways downstream of Ras and regulation of the cell cycle and apoptotic proteins in tumors derived from the implanted transformants. We found that the K12V oncogene induces a more aggressive tumorigenic phenotype than the K12D oncogene, whereas K12C does not induce tumors in this model. Thus, K12V mutant tumors proliferate about seven times faster, and have higher cellularity and mitotic rates than the K12D mutant tumors. A molecular analysis of the induced tumors shows that the K12V mutant protein interacts with Raf-1 and transduces signals mainly through the Erk pathway. Unexpectedly, in tumors induced by the K12D oncogene, the K-Ras mutant protein does not interact with Raf-1 nor activates the Erk canonical pathway. Instead, it transduces signals through the PI3K/Akt, JNK, p38 and FAK pathways. Finally, the higher growth rate of the K12V tumors associates with enhanced Rb phosphorylation, and PCNA and Cyclin B upregulation, consistent with faster G1/S and G2/M transitions, without alteration of apoptotic regulation.
Received November 23, 2005
Revised March 24, 2006
Accepted April 15, 2006
CANCER BIOLOGY
K-Ras Asp12 mutant neither interacts with Raf, nor signals through Erk, and is less tumorigenic than K-Ras Val12
Maria Virtudes Céspedes 1,
Francesc Josep Sancho 2,
Silvia Guerrero 3,
Matilde Parreño 1,
Isolda Casanova 1,
Miguel Angel Pavón 1,
Eugenio Marcuello 4,
Manuel Trias 5,
Marta Cascante 6,
Gabriel Capellà 7,
and
Ramon Mangues 1 *
2 Depatment of Pathology, HSCSP, Spain
3 Advanced in vitro cell technologies, Parc Científic de Barcelona, Spain
4 Department of Medical Oncology, HSCSP, Spain
5 Department of Surgery, HSCSP, Spain
6 Centre Recerca en Química Teòrica-Parc Cientific de Barcelona, IDIBAPS, University of Barcelona, Spain
7 Laboratori de Recerca Traslacional, IDIBELL-Institut Català d'Oncologia, Barcelona, Spain
Ramon Mangues, E-mail: rmangues{at}santpau.es
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