Open AccessThe promoters of human cell cycle genes integrate signals from two tumor suppressive pathways during cellular transformation
Author(s) -
Tabach Yuval,
Milyavsky Michael,
Shats Igor,
Brosh Ran,
Zuk Or,
Yitzhaky Assif,
Mantovani Roberto,
Domany Eytan,
Rotter Varda,
Pilpel Yitzhak
Publication year - 2005
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.1038/msb4100030
Subject(s) - biology , e2f , cell cycle , gene , transcription factor , transformation (genetics) , gene expression profiling , computational biology , promoter , mitosis , transcription (linguistics) , microbiology and biotechnology , regulation of gene expression , gene expression , genetics , linguistics , philosophy
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.