The promoters of human cell cycle genes integrate signals from two tumor suppressive pathways during cellular transformation.

Yuval Tabach*, Michael Milyavsky, Igor Shats, Ran Brosh, O. Zuk, Assif Yitzhaky, Roberto Mantovani, Eytan Domany, Varda Rotter, Yitzhak Pilpel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)2005.0022
JournalMolecular Systems Biology
Volume1
DOIs
StatePublished - 2005
Externally publishedYes

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