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Identification of direct p73 target genes combining DNA microarray and chromatin immunoprecipitation analyses
Giulia Fontemaggi1, Itai Kela, Ninette Amariglio
1Department of Experimental Oncology, Regina Elena Cancer Institute, Rome 00158, Italy.
Abstract:
The newly discovered p53 family member, p73, has a striking homology to p53 in both sequence and modular structure. Ectopic expression of p73 promotes transcription of p53 target genes and recapitulates the most characterized p53 biological effects such as growth arrest, apoptosis, and differentiation. Unlike p53-deficient mice that develop normally but are subject to spontaneous tumor formation, p73-deficient mice exhibit severe defects in the development of central nervous system and suffer from inflammation but are not prone to tumor development. These phenotypes suggest different biological activities mediated by p53 and p73 that might reflect activation of specific sets of target genes. Here, we have analyzed the gene expression profile of H1299 cells after p73alpha or p53 activation using oligonucleotide microarrays capable of detecting approximately 11,000 mRNA species. Our results indicate that p73alpha and p53 activate both common and distinct groups of genes. We found 141 and 320 genes whose expression is modulated by p73alpha and p53, respectively. p73alpha up-regulates 85 genes, whereas p53 induces 153 genes, of which 27 are in common with p73alpha. Functional classification of these genes reveals that they are involved in many aspects of cell function ranging from cell cycle and apoptosis to DNA repair. Furthermore, we report that some of the up-regulated genes are directly activated by p73alpha or p53.
Insights
The tumor suppressor protein p73 (p73) and p53 activate distinct gene sets, impacting cell functions like apoptosis and DNA repair. This reveals unique roles for p73 and p53 in cellular processes.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- p73 is a p53 family member with structural and functional similarities to p53.
- p53 and p73 exhibit distinct in vivo phenotypes, suggesting differential target gene activation.
- Understanding shared and unique targets is crucial for deciphering their roles in cellular regulation.
Purpose of the Study:
- To compare the gene expression profiles induced by p73alpha and p53.
- To identify common and distinct target genes regulated by p73alpha and p53.
- To functionally classify the genes modulated by these proteins.
Main Methods:
- Gene expression profiling using oligonucleotide microarrays.
- Activation of p73alpha and p53 in H1299 cells.
- Analysis of approximately 11,000 mRNA species.
Main Results:
- p73alpha modulated 141 genes, while p53 modulated 320 genes.
- p73alpha upregulated 85 genes, and p53 upregulated 153 genes, with 27 common targets.
- Functional classification revealed involvement in cell cycle, apoptosis, and DNA repair.
Conclusions:
- p73alpha and p53 regulate overlapping and distinct sets of genes.
- These findings highlight differential roles of p73 and p53 in cellular functions.
- Some upregulated genes are direct transcriptional targets of p73alpha or p53.