title: Integrated high-throughput analysis identifies Sp1 as a crucial determinant of p53-mediated apoptosis.
abstract: The restoration of p53 tumor suppressor function is a promising therapeutic strategy to combat cancer. However, the biological outcomes of p53 activation, ranging from the promotion of growth arrest to the induction of cell death, are hard to predict, which limits the clinical application of p53-based therapies. In the present study, we performed an integrated analysis of genome-wide short hairpin RNA screen and gene expression data and uncovered a previously unrecognized role of Sp1 as a central modulator of the transcriptional response induced by p53 that leads to robust induction of apoptosis. Sp1 is indispensable for the pro-apoptotic transcriptional repression by p53, but not for the induction of pro-apoptotic genes. Furthermore, the p53-dependent pro-apoptotic transcriptional repression required the co-binding of Sp1 to p53 target genes. Our results also highlight that Sp1 shares with p53 a common regulator, MDM2, which targets Sp1 for proteasomal degradation. This uncovers a new mechanism of the tight control of apoptosis in cells. Our study advances the understanding of the molecular basis of p53-mediated apoptosis and implicates Sp1 as one of its key modulators. We found that small molecules reactivating p53 can differentially modulate Sp1, thus providing insights into how to manipulate p53 response in a controlled way.
authors: Department of Microbiology, Tumor and Cell Biology Biology (MTC), Karolinska Institutet, 17177 Stockholm, Sweden.
authors: H
authors: H
authors: Li
authors: College of Life Science, Northeast Agricultural University, Mucai Street 59, Harbin 150030, PR China.
authors: Y
authors: Y
authors: Zhang
authors: Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors: A
authors: A
authors: Ströse
authors: Cellecta, Inc., 320 Logue Avenue, Mountain View, CA 94043, USA.
authors: D
authors: D
authors: Tedesco
authors: Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors: K
authors: K
authors: Gurova
authors: Department of Microbiology, Tumor and Cell Biology Biology (MTC), Karolinska Institutet, 17177 Stockholm, Sweden.
authors: G
authors: G
authors: Selivanova
mesh_terms: D017209:Apoptosis; D045325:HCT116 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D016159:Tumor Suppressor Protein p53