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Jnk2 effects on tumor development, genetic instability and replicative stress in an oncogene-driven mouse mammary

Peila Chen1, Jamye F O'Neal, Nancy D Ebelt

  • 1Division of Pharmacology and Toxicology, Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, United States of America.

Plos One
|May 11, 2010
PubMed

Insights

JNK2 deficiency accelerates mammary tumor development and increases genomic instability in mice. JNK2 is crucial for DNA damage response and preventing replicative stress.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • Oncogenes drive cell proliferation, leading to replicative stress, DNA damage, and genomic instability.
  • c-Jun N-terminal kinase (JNK) proteins are activated by cellular stress, but JNK isoform roles in tumor development are understudied.

Purpose of the Study:

  • To investigate the role of JNK2 in mammary tumor development and genomic stability.
  • To elucidate the mechanisms by which JNK2 influences DNA damage response and cell cycle progression.

Main Methods:

  • Utilized jnk2 knockout and wildtype mice expressing the Polyoma Middle T Antigen (PyV MT) transgene.
  • Assessed tumor development, multiplicity, aneuploidy, and DNA damage response markers (pH2AX, 53BP1 foci).
  • Performed comparative genomic hybridization (CGH) and in vitro cell-based assays (BrdU incorporation, protein expression analysis, RPA localization).

Main Results:

  • jnk2 knockout mice exhibited earlier mammary tumor onset and higher tumor multiplicity compared to wildtype controls.
  • Loss of JNK2 was associated with increased tumor aneuploidy, reduced DNA damage response, and heightened genomic instability.
  • In vitro studies showed jnk2 deficiency impaired response to replicative stress and DNA damage, affecting cell cycle regulators.

Conclusions:

  • JNK2 plays a critical role in preventing mammary tumor development and maintaining genomic stability.
  • JNK2 is essential for coordinating cell cycle progression and DNA damage repair mechanisms in response to stress.
  • JNK2 acts early in the DNA damage response pathway, facilitating the recruitment of repair proteins.

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