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NF-kappaB RelA opposes epidermal proliferation driven by TNFR1 and JNK

Jennifer Y Zhang1, Cheryl L Green, Shiying Tao

  • 1VA Palo Alto Healthcare System, Palo Alto, California 94305, USA.

Genes & Development
|January 16, 2004
PubMed

Insights

Nuclear factor-kappa B (NF-kappaB) RelA restrains epidermal growth by antagonizing tumor necrosis factor receptor 1 (TNFR1)-JNK signals. Its deficiency causes TNFR1-dependent skin hyperplasia, highlighting its role in skin homeostasis.

Area of Science:

  • Dermatology
  • Molecular Biology
  • Cancer Research

Background:

  • NF-kappaB inhibition is linked to epidermal tumorigenesis, but its role in normal skin homeostasis is unclear.
  • Previous studies were limited by embryonic lethality in mice lacking NF-kappaB RelA.
  • Understanding RelA's function in epidermis is crucial for cancer research.

Purpose of the Study:

  • To investigate the role of NF-kappaB RelA in epidermal homeostasis and growth regulation.
  • To overcome the challenge of embryonic lethality by generating developmentally mature RelA(-/-) skin.
  • To elucidate the molecular mechanisms underlying epidermal hyperplasia in the absence of RelA.

Main Methods:

  • Generation of developmentally mature RelA(-/-) mouse skin models.
  • Analysis of epidermal hyperplasia, differentiation, inflammation, and apoptosis.
  • Investigating the role of tumor necrosis factor receptor 1 (TNFR1) and JNK signaling pathways.

Main Results:

  • RelA(-/-) epidermis exhibited hyperplasia without abnormal differentiation, inflammation, or apoptosis.
  • Hyperproliferation was dependent on TNFR1 signaling, as Tnfr1 deletion normalized cell division.
  • TNFR1-dependent JNK activation was observed in RelA(-/-) epidermis, and JNK inhibition abolished hyperproliferation.

Conclusions:

  • RelA antagonizes TNFR1-JNK proliferative signals in the epidermis.
  • RelA plays a critical, nonredundant role in restraining epidermal growth.
  • These findings clarify the function of NF-kappaB RelA in skin homeostasis and provide insights into epidermal development.

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