Argininosuccinate synthase 1 is an intrinsic Akt repressor transactivated by p53

Sci Adv. 2017 May 19;3(5):e1603204. doi: 10.1126/sciadv.1603204. eCollection 2017 May.

Abstract

The transcription factor p53 is at the core of a built-in tumor suppression system that responds to varying degrees of stress input and is deregulated in most human cancers. Befitting its role in maintaining cellular fitness and fidelity, p53 regulates an appropriate set of target genes in response to cellular stresses. However, a comprehensive understanding of this scheme has not been accomplished. We show that argininosuccinate synthase 1 (ASS1), a citrulline-aspartate ligase in de novo arginine synthesis pathway, was directly transactivated by p53 in response to genotoxic stress, resulting in the rearrangement of arginine metabolism. Furthermore, we found that x-ray irradiation promoted the systemic induction of Ass1 and concomitantly increased plasma arginine levels in p53+/+ mice but not in p53-/- mice. Notably, Ass1+/- mice exhibited hypersensitivity to whole-body irradiation owing to increased apoptosis in the small intestinal crypts. Analyses of ASS1-deficient cells generated using the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated 9) system revealed that ASS1 plays a pivotal role in limiting Akt phosphorylation. In addition, aberrant activation of Akt resulting from ASS1 loss disrupted Akt-mediated cell survival signaling activity under genotoxic stress. Building on these results, we demonstrated that p53 induced an intrinsic Akt repressor, ASS1, and the perturbation of ASS1 expression rendered cells susceptible to genotoxic stress. Our findings uncover a new function of p53 in the regulation of Akt signaling and reveal how p53, ASS1, and Akt are interrelated to each other.

Keywords: ASS1; Akt; p53.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / radiation effects
  • Argininosuccinate Synthase / genetics
  • Argininosuccinate Synthase / metabolism*
  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Cell Survival / radiation effects
  • Humans
  • Intestine, Small / metabolism
  • Intestine, Small / pathology
  • Mice
  • Mice, Knockout
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / radiation effects*
  • Transcriptional Activation / genetics
  • Transcriptional Activation / radiation effects*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • X-Rays / adverse effects*

Substances

  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-akt
  • Argininosuccinate Synthase