Gene expression profiling in melanoma identifies novel downstream effectors of p14ARF.
p14ARF is inactivated by deletions/mutations in many cancer types and can suppress cell growth by both p53-dependent and p53-independent mechanisms. To identify novel downstream effectors of p14ARF, we used gene expression profiling as a primary screening tool to select candidates for follow up validation studies using in vitro cell-based assays. Gene expression profiles of a panel of 35 melanoma cell lines with either wild-type (n = 12) or mutant (n = 23) p14ARF were compared to identify genes associated with inactivation of p14ARF. Analysis of the microarray data identified 1,316 probe sets that were significantly (p < 0.01) differentially expressed between the p14ARF wild-type and mutant cell lines. Pathway analysis of these genes showed an overrepresentation of many receptor-mediated signal transduction pathways, e.g. TGFbeta, EGF, HGF, PDGF, MAPK, Wnt and integrin pathways. A number of components of these pathways, including FLRT3, RUNX2, MIG-6 and SMURF2 were confirmed as downstream targets of p14ARF using p14ARF-inducible cell lines and RNAi. We propose that regulation of these genes may contribute to melanoma development when p14ARF function is lost.
Packer
Leisl M
LM
Oncogenomics Laboratory, Queensland Institute of Medical Research, Brisbane, Australia. Leisl.Packer@qimr.edu.au
Pavey
Sandra J
SJ
Boyle
Glen M
GM
Stark
Mitchell S
MS
Ayub
Ana L
AL
Rizos
Helen
H
Hayward
Nicholas K
NK
D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics; D008954:Models, Biological; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
D050659:Core Binding Factor Alpha 1 Subunit; C404492:FLRT3 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C493709:RUNX2 protein, human; D025803:Tumor Suppressor Protein p14ARF