Functional analysis and secondary expressionprofiling of candidate genes deregulated inconjunction with oncogenic Ras signaling

摘要

Mutated RAS proteins exert their oncogenic activity through profound alterationsof the transcriptional program. Expression profiling studies contrasting thetranscriptomes of cell lines transformed by introduction of mutant RAS genes andnormal precursors have yielded a large number of target genes that appear to bederegulated by oncogenic RAS-mediated signal transduction. Sets of up-regulatedand down-regulated genes were identified in fibroblasts (Huang et al., 2003; Ordwayet al., 2004; Teramoto et al., 2003; Vasseur et al., 2003; Zuber et al., 2000), epithelialcells (Desai et al., 2002; Jechlinger et al., 2003; Liu et al., 2004; Tchernitsa et al.,2004; Yoon et al., 2002), mast cells (Brem et al., 2001) and glial precursors(Rajasekhar and Holland, 2004). Gene sets overlap only partially, indicating that thetranscriptional response to Ras signaling involves complex alterations which may belargely governed by the genetic programs of cells the oncogene is targeted to or by alternative usage of signaling pathways downstream of Ras (Hamad et al., 2002).Moreover, results from microarray analysis, the technology most often applied forexpression profiling, may be dependent on the use of different platforms andbioinformatic data processing (Tan et al., 2003). Perhaps most importantly, theexperimental parameters of studies on Ras-dependent transcriptional alterationsdiffered significantly, thus hampering comparisons among them.