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The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis

K Evangelou1, J Bartkova, A Kotsinas

  • 1Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece.

Cell Death and Differentiation
|July 16, 2013
PubMed

Insights

The alternative reading frame (ARF) tumor suppressor is activated later than the DNA damage response (DDR) during cancer progression. ARF acts as a delayed barrier against tumor development, requiring higher oncogenic stress signals than DDR.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Oncogenic stimuli activate the DNA damage response (DDR) and alternative reading frame (ARF) tumor suppressor.
  • Both pathways can activate the p53 pathway, a critical barrier to tumor progression.
  • The timing and signal thresholds for ARF induction versus DDR activation during tumorigenesis are not well understood.

Purpose of the Study:

  • To investigate the temporal relationship and signal thresholds for ARF induction and DDR activation during tumorigenesis.
  • To compare these events in various preclinical and clinical cancer models.

Main Methods:

  • Analysis of mouse models of premalignant and malignant lesions in the urinary bladder, colon, pancreas, and skin.
  • Examination of human clinical samples from early and progressive lesions of the urinary bladder, head and neck, skin, and pancreas.
  • Mechanistic studies using epithelial and fibroblast cell models exposed to oncogenes.

Main Results:

  • ARF expression consistently occurred at later stages of tumor progression than DDR activation or p16(INK4A) induction across all models.
  • Similar temporal patterns were observed in human cancer lesions.
  • Mechanistic studies revealed that ARF upregulation requires a higher oncogenic stress threshold (at least two oncogenic 'hits') compared to DDR activation.

Conclusions:

  • ARF induction is a delayed event in tumorigenesis relative to DDR activation.
  • ARF functions as a complementary, delayed barrier to tumor development, responding to more significant oncogenic stress.
  • This suggests a stepwise model of tumor suppression involving distinct responses to escalating oncogenic stimuli.

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