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Inhibition of CREB function in mouse epidermis reduces papilloma formation

Julian Rozenberg1, Vikas Rishi, Andras Orosz

  • 1Laboratory of Metabolism, National Cancer Institute, NIH, 37 Convent Drive, Room 2D24, Bethesda, MD 20892, USA.

Molecular Cancer Research : MCR
|May 14, 2009
PubMed

Insights

Inhibiting cAMP-responsive element binding protein (CREB) function in mouse skin reduces papilloma formation during chemical carcinogenesis. This suggests CREB is crucial for early tumor development and offers a potential cancer prevention strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • cAMP-responsive element binding protein (CREB) is a transcription factor involved in various cellular processes.
  • Dysregulation of CREB activity is implicated in the development of several cancers.
  • Understanding CREB's role in skin carcinogenesis is crucial for developing targeted prevention strategies.

Purpose of the Study:

  • To investigate the role of CREB in skin carcinogenesis using a conditional dominant-negative A-CREB mouse model.
  • To determine if inhibiting CREB function impacts tumor initiation and progression in chemically induced skin cancer.
  • To elucidate the molecular mechanisms by which CREB influences oncogenesis in epidermal cells.

Main Methods:

  • Generation of a double transgenic tetracycline-inducible system to conditionally express A-CREB in mouse basal epidermis under the keratin 5 promoter.
  • Utilized a 7,12-dimethylbenz(a)anthracene (DMBA)/phorbol-12-myristate-13-acetate (PMA) two-stage skin carcinogenesis protocol.
  • Analyzed papilloma formation, oncogenic H-Ras mutations, apoptosis, and cell cycle protein expression in A-CREB expressing and wild-type mice.

Main Results:

  • Conditional expression of A-CREB in mouse epidermis significantly reduced papilloma formation by 5-fold compared to wild-type controls during chemical carcinogenesis.
  • A-CREB expression did not prevent papilloma formation when administered after DMBA treatment, indicating CREB's role in early stages.
  • Absence of oncogenic H-Ras mutations in A-CREB expressing skin suggests CREB inhibition prevents DMBA-induced mutagenesis or eliminates oncogenic cells.
  • A-CREB expression induced apoptosis in v-Ras(Ha)-infected keratinocytes and suppressed cyclin B1 and cyclin D1 expression.

Conclusions:

  • CREB plays a critical role in the early stages of skin papilloma formation.
  • Inhibiting CREB function through dominant-negative strategies presents a promising approach for skin cancer prevention.
  • Targeting CREB signaling pathways may offer a novel therapeutic strategy for oncological conditions.

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