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 R Sertil, Antonis Kourtidis, Douglas S. Conklin, Julio A. Aguirre-Ghiso

Research output: Contribution to journalArticle

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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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p38 Mitogen-Activated Protein Kinases
Transcription Factors
Down-Regulation
Neoplasms
Gene Regulatory Networks
RNA Interference
Squamous Cell Carcinoma
Phosphotransferases
Neoplasm Metastasis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Computational identification of a p38 SAPK-regulated transcription factor network required for tumor cell quiescence. / Adam, Alejandro P.; George, Ajish; Schewe, Denis; Bragado, Paloma; Iglesias, Bibiana V.; Sertil, Aparna R; Kourtidis, Antonis; Conklin, Douglas S.; Aguirre-Ghiso, Julio A.

In: Cancer Research, Vol. 69, No. 14, 15.07.2009, p. 5664-5672.

Research output: Contribution to journalArticle

Adam, AP, George, A, Schewe, D, Bragado, P, Iglesias, BV, Sertil, AR, Kourtidis, A, Conklin, DS & Aguirre-Ghiso, JA 2009, 'Computational identification of a p38 SAPK-regulated transcription factor network required for tumor cell quiescence', Cancer Research, vol. 69, no. 14, pp. 5664-5672. https://doi.org/10.1158/0008-5472.CAN-08-3820
Adam, Alejandro P. ; George, Ajish ; Schewe, Denis ; Bragado, Paloma ; Iglesias, Bibiana V. ; Sertil, Aparna R ; Kourtidis, Antonis ; Conklin, Douglas S. ; Aguirre-Ghiso, Julio A. / Computational identification of a p38 SAPK-regulated transcription factor network required for tumor cell quiescence. In: Cancer Research. 2009 ; Vol. 69, No. 14. pp. 5664-5672.
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