Computational identification of a p38 SAPK-regulated transcription factor network required for tumor cell quiescence

Alejandro P. Adam, Ajish George, Denis Schewe, Paloma Bragado, Bibiana V. Iglesias, Aparna C. Ranganathan, Antonis Kourtidis, Douglas S. Conklin, Julio A. Aguirre-Ghiso

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77 Scopus citations

Abstract

The stress-activated kinase p38 plays key roles in tumor suppression and induction of tumor cell dormancy. However, the mechanisms behind these functions remain poorly understood. Using computational tools, we identified a transcription factor (TF) network regulated by p38α/β and required for human squamous carcinoma cell quiescence in vivo. We found that p38 transcriptionally regulates a core network of 46 genes that includes 16 TFs. Activation of p38-induced the expression of the TFs p53 and BHLHB3, while inhibiting c-Jun and FoxM1 expression. Furthermore, induction of p53 by p38 was dependent on c-Jun down-regulation. Accordingly, RNAi down-regulation of BHLHB3 or p53 interrupted tumor cell quiescence, while down-regulation of c-Jun or FoxM1 or overexpression of BHLHB3 in malignant cells mimicked the onset of quiescence. Our results identify components of the regulatory mechanisms driving p38-induced cancer cell quiescence. These may regulate dormancy of residual disease that usually precedes the onset of metastasis in many cancers.

Original languageEnglish (US)
Pages (from-to)5664-5672
Number of pages9
JournalCancer Research
Volume69
Issue number14
DOIs
StatePublished - Jul 15 2009
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Adam, A. P., George, A., Schewe, D., Bragado, P., Iglesias, B. V., Ranganathan, A. C., Kourtidis, A., Conklin, D. S., & Aguirre-Ghiso, J. A. (2009). Computational identification of a p38 SAPK-regulated transcription factor network required for tumor cell quiescence. Cancer Research, 69(14), 5664-5672. https://doi.org/10.1158/0008-5472.CAN-08-3820