The promoters of human cell cycle genes integrate signals from two tumor suppressive pathways during cellular transformation.
Deciphering regulatory events that drive malignant transformation represents a major challenge for systems biology. Here, we analyzed genome-wide transcription profiling of an in vitro cancerous transformation process. We focused on a cluster of genes whose expression levels increased as a function of p53 and p16(INK4A) tumor suppressors inactivation. This cluster predominantly consists of cell cycle genes and constitutes a signature of a diversity of cancers. By linking expression profiles of the genes in the cluster with the dynamic behavior of p53 and p16(INK4A), we identified a promoter architecture that integrates signals from the two tumor suppressive channels and that maps their activity onto distinct levels of expression of the cell cycle genes, which, in turn, correspond to different cellular proliferation rates. Taking components of the mitotic spindle as an example, we experimentally verified our predictions that p53-mediated transcriptional repression of several of these novel targets is dependent on the activities of p21, NFY, and E2F. Our study demonstrates how a well-controlled transformation process allows linking between gene expression, promoter architecture, and activity of upstream signaling molecules.
Tabach
Yuval
Y
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Milyavsky
Michael
M
Shats
Igor
I
Brosh
Ran
R
Zuk
Or
O
Yitzhaky
Assif
A
Mantovani
Roberto
R
Domany
Eytan
E
Rotter
Varda
V
Pilpel
Yitzhak
Y
D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000502:physiology; D002455:Cell Division; D002461:Cell Line, Transformed / Q000378:metabolism / Q000637:transplantation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019295:Computational Biology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D018816:Genes, cdc; D019942:Genes, p16; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid; D008941:Spindle Apparatus / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D019098:Telomerase