Integrative genomics revealed RAI3 is a cell growth-promoting gene and a novel P53 transcriptional target.
In this study, differential gene expression between normal human mammary epithelial cells and their malignant counterparts (eight well established breast cancer cell lines) was studied using Incyte GeneAlbum 1-6, which contains 65,873 cDNA clones representing 33,515 individual genes. 3,152 cDNAs showed a > or =3.0-fold expression level change in at least one of the human breast cancer cell lines as compared with normal human mammary epithelial cells. Integration of breast tumor gene expression data with the genes in the tumor suppressor p53 signaling pathway yielded 128 genes whose expression is altered in breast tumor cell lines and in response to p53 expression. A hierarchical cluster analysis of the 128 genes revealed that a significant portion of genes demonstrate an opposing expression pattern, i.e. p53-activated genes are down-regulated in the breast tumor lines, whereas p53-repressed genes are up-regulated. Most of these genes are involved in cell cycle regulation and/or apoptosis, consistent with the tumor suppressor function of p53. Follow-up studies on one gene, RAI3, suggested that p53 interacts with the promoter of RAI3 and repressed its expression at the onset of apoptosis. The expression of RAI3 is elevated in most tumor cell lines expressing mutant p53, whereas RAI3 mRNA is relatively repressed in the tumor cell lines expressing wild-type p53. Furthermore, ectopic expression of RAI3 in 293 cells promotes anchorage-independent growth and small interfering RNA-mediated depletion of RAI3 in AsPc-1 pancreatic tumor cells induces cell morphological change. Taken together, these data suggest a role for RAI3 in tumor growth and demonstrate the predictive power of integrative genomics.
Wu
Qun
Q
Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Ding
Wei
W
Mirza
Asra
A
Van Arsdale
Tish
T
Wei
Iris
I
Bishop
W Robert
WR
Basso
Andrea
A
McClanahan
Terri
T
Luo
Lin
L
Kirschmeier
Paul
P
Gustafson
Eric
E
Hernandez
Marco
M
Liu
Suxing
S
D000362:Agar / Q000737:chemistry; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D016000:Cluster Analysis; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D023281:Genomics / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism; D008957:Models, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
D018076:DNA, Complementary; C116760:GPRC5A protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D016159:Tumor Suppressor Protein p53; D000362:Agar