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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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c-Jun NH2-terminal kinase 2 is required for Ras transformation independently of activator protein 1

Christina Nielsen1, Jacob Thastrup, Trine Bøttzauw

  • 1Apoptosis Department and Centre for Genotoxic Stress, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.

Cancer Research
|January 11, 2007
PubMed

Insights

The study reveals that c-Jun-NH(2)-terminal kinase 2 (JNK2) is essential for H-Ras oncogene-driven cancer transformation. Inhibiting JNK2 significantly blocks tumor formation, identifying it as a potential therapeutic target in Ras-driven cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Active Ras oncogene drives approximately 30% of human cancers, but its transformation mechanisms are poorly understood.
  • The role of specific c-Jun-NH(2)-terminal kinase (JNK) isoforms in Ras-mediated transformation remains largely unelucidated.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying H-Ras-mediated cellular transformation.
  • To determine the specific role of JNK isoforms, particularly JNK2, in Ras oncogene-driven tumorigenesis.

Main Methods:

  • Utilized JNK2-deficient (Jnk2-/-) and wild-type murine embryonic fibroblasts (MEFs).
  • Assessed cellular transformation through in vitro colony formation and soft agar assays.
  • Evaluated tumor formation in vivo using immunodeficient mice.
  • Employed RNA interference to deplete JNK2 in wild-type MEFs.
  • Investigated the impact of HPV E6, SV40 large T antigen, and c-Myc coexpression.

Main Results:

  • JNK2 deficiency severely inhibited H-Ras-mediated colony formation, soft agar growth, and tumor formation in mice.
  • RNA interference-mediated JNK2 depletion also impaired Ras transformation.
  • JNK2-deficient cells retained p53 signaling inactivation (loss of p19Arf) but still exhibited transformation defects.
  • Coexpression with SV40 large T antigen or c-Myc could overcome the JNK2-deficiency-related transformation defect.
  • Surprisingly, JNK2-deficient cells showed increased AP-1 activity and c-Jun levels, suggesting JNK2's key target is not AP-1.

Conclusions:

  • JNK2 is a critical kinase required for H-Ras-mediated cellular transformation.
  • JNK2 plays a crucial role in Ras-driven tumorigenesis, independent of p53 pathway inactivation.
  • The findings identify JNK2 as a potential therapeutic vulnerability in Ras-driven cancers.

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