Analysis of TAp73-Dependent Signaling via Omics Technologies

• Published in: Journal of proteome research 2013-09, Vol.12 (9), p.4207-4220
• Main Authors: D’Alessandro, Angelo, Marrocco, Cristina, Rinalducci, Sara, Peschiaroli, Angelo, Timperio, Anna Maria, Bongiorno-Borbone, Lucilla, Finazzi Agrò, Alessandro, Melino, Gerry, Zolla, Lello
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Cell Line, Tumor; Cell Proliferation; Cell Survival; Citric Acid Cycle; DNA-Binding Proteins - metabolism; Endoplasmic Reticulum Stress; Gene Expression Regulation; Glutathione - metabolism; Glycolysis; Homeostasis; Humans; Lipid Metabolism; Metabolome; Molecular Sequence Data; Nuclear Proteins - metabolism; Pentose Phosphate Pathway; Phosphatidylinositols - metabolism; Phosphoproteins - chemistry; Phosphoproteins - metabolism; Proteolysis; Proteome - chemistry; Proteome - metabolism; Proteomics; Purines - metabolism; Signal Transduction; Systems Biology; Transcription, Genetic; Tumor Protein p73; Tumor Suppressor Proteins - metabolism
• ISSN: 1535-3893; 1535-3907
• DOI: 10.1021/pr4005508

Transactivation-proficient (TA) p73 is a transcription factor belonging to the p53 family, which regulates a variety of biological processes, including neurogenesis, differentiation, apoptosis, and DNA damage checkpoint response. In the present study, we adopted multiple Omics approaches, based upon the simultaneous application of metabolomics, lipidomics, and proteomics, in order to dissect the intracellular pathways activated by p73. As cellular model, we utilized a clone of the human osteosarcoma SAOS-2 cell line that allows the expression of TAp73α in an inducible manner. We found that TAp73α promoted mitochondrial activity (accumulation of metabolic intermediates and up-regulation of proteins related to the Krebs cycle), boosted glutathione homeostasis, increased arginine–citrulline–NO metabolism, altered purine synthesis, and promoted the pentose phosphate pathway toward NADPH accumulation for reducing and biosynthetic purposes. Indeed, lipid metabolism was driven toward the accumulation and oxidation of long-chain fatty acids with pro-apoptotic potential. In parallel, the expression of TAp73α was accompanied by the dephosphorylation of key proteins of the mitotic spindle assembly checkpoint. In conclusion, the obtained results confirm existing evidence from transcriptomics analyses and suggest a role for TAp73α in the regulation of cellular metabolism, cell survival, and cell growth.