The coactivator CRTC1 promotes cell proliferation and transformation via AP-1

Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1445-50. doi: 10.1073/pnas.0808749106. Epub 2009 Jan 21.


Regulation of gene expression in response to mitogenic stimuli is a critical aspect underlying many forms of human cancers. The AP-1 complex mediates the transcriptional response to mitogens, and its deregulation causes developmental defects and tumors. We report that the coactivator CRTC1 cyclic AMP response element-binding protein (CREB)-regulated transcription coactivator 1 is a potent and indispensable modulator of AP-1 function. After exposure of cells to the AP-1 agonist 12-O-tetradecanoylphorbol-13-acetate (TPA), CRTC1 is recruited to AP-1 target gene promoters and associates with c-Jun and c-Fos to activate transcription. CRTC1 consistently synergizes with the proto-oncogene c-Jun to promote cellular growth, whereas AP-1-dependent proliferation is abrogated in CRTC1-deficient cells. Remarkably, we demonstrate that CRTC1-Maml2 oncoprotein, which causes mucoepidermoid carcinomas, binds and activates both c-Jun and c-Fos. Consequently, ablation of AP-1 function disrupts the cellular transformation and proliferation mediated by this oncogene. Together, these data illustrate a novel mechanism required to couple mitogenic signals to the AP-1 gene regulatory program.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation*
  • Cell Transformation, Neoplastic*
  • DNA-Binding Proteins / metabolism
  • HeLa Cells
  • Humans
  • Immunoprecipitation
  • Nuclear Proteins / metabolism
  • Promoter Regions, Genetic
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-fos / physiology
  • Proto-Oncogene Proteins c-jun / physiology
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tetradecanoylphorbol Acetate / pharmacology
  • Trans-Activators
  • Transcription Factor AP-1 / physiology*
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transcriptional Activation


  • CRTC1 protein, human
  • DNA-Binding Proteins
  • MAML2 protein, human
  • MAS1 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Trans-Activators
  • Transcription Factor AP-1
  • Transcription Factors
  • Tetradecanoylphorbol Acetate