Identification of SULF2 as a novel transcriptional target of p53 by use of integrated genomic analyses.
Microarray analysis has been useful for identifying the targets of many transcription factors. However, gene expression changes in response to transcription factor perturbation reveal both direct transcriptional targets and secondary gene regulation. By integrating RNA interference, gene expression profiling, and chromatin immunoprecipitation technologies, we identified a set of 32 direct transcriptional targets of the tumor suppressor p53. Of these 32 genes, 11 are not currently associated with the core p53 pathway. From among these novel pathway members, we focused on understanding the connection between p53 and SULF2, which encodes an extracellular heparan sulfate 6-O-endosulfatase that modulates the binding of growth factors to their cognate receptors and that has been shown to function as a tumor suppressor. Genetic and pharmacologic perturbation of p53 directly influences SULF2 expression, and similar to silencing of TP53, RNA interference-mediated suppression of SULF2 results in an impaired senescence response of cells to genotoxic stress. Thus, our integrated genomic approach has led to the identification of a novel mediator of p53 network biology.
Chau
B Nelson
BN
Rosetta Inpharmatics LLC, a wholly owned subsidiary of Merck & Co, Inc, Seattle, Washington 98109, USA.
Diaz
Robert L
RL
Saunders
Matthew A
MA
Cheng
Chun
C
Chang
Aaron N
AN
Warrener
Paul
P
Bradshaw
Jeffrey
J
Linsley
Peter S
PS
Cleary
Michele A
MA
D000970:Antineoplastic Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D045744:Cell Line, Tumor; D017931:DNA Primers; D005784:Gene Amplification; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D015894:Genome, Human; D015698:Genomic Library; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012516:Osteosarcoma / Q000235:genetics; D016133:Polymerase Chain Reaction; D013429:Sulfatases; D015238:Sulfotransferases / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D000970:Antineoplastic Agents; D017931:DNA Primers; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D015238:Sulfotransferases; C470792:SULF2 protein, human; D013429:Sulfatases