Transcriptional networks of knockout cell lines identify functional specificities of H-Ras and N-Ras: significant involvement of N-Ras in biotic and defense responses

被引:29
作者
Castellano, E. [1 ]
De Las Rivas, J. [1 ]
Guerrero, C. [1 ]
Santos, E. [1 ]
机构
[1] Univ Salamanca, Ctr Invest Canc, CSIC, USAL,Inst Biol Mol & Celular Canc, Salamanca 37007, Spain
关键词
H-Ras; N-Ras; microarray; genomics; transcriptome; cluster analysis; differential gene expression;
D O I
10.1038/sj.onc.1209845
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 [生物化学与分子生物学]; 081704 [应用化学];
摘要
We characterized differential gene expression profiles of fibroblast cell lines harboring single or double-homozygous null mutations in H-ras and N-ras. Whereas the expression level of the individual H-, N- and K-ras genes appeared unaffected by the presence or absence of the other ras loci, significant differences were observed between the expression profiles of cells missing N-ras and/or H-ras. Absence of N-ras produced much stronger effects than absence of H-ras over the pro. le of the cellular transcriptome. N-ras(-/-) and H-ras(-/-). broblasts displayed rather antagonistic expression profiles and the transcriptome of H-ras(-/-) cells was significantly closer to that of wild-type. broblasts than to that of N- ras(-/-) cells. Classifying all differentially expressed genes into functional categories suggested specific roles for H-Ras and N-Ras. It was particularly strikingin N-ras(-/-) cells the upregulation of a remarkable number of immunity-related genes, as well as of several loci involved in apoptosis. Reverse-phase protein array assays demonstrated in the same N- ras(-/-) cells the overexpression and nuclear migration of tyrosine phosphorylated signal transducer and activator of transcription 1 (Stat1) which was concomitant with transcriptional activation mediated by interferon-stimulated response elements. Significantly enhanced numbers of apoptotic cells were also detected in cultures of N-ras(-/-) cells. Our data support the notion that different Ras isoforms play functionally distinct cellular roles and indicate that N-Ras is significantly involved in immune modulation/host defense and apoptotic responses.
引用
收藏
页码:917 / 933
页数:17
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