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The FoxO3a gene is a key negative target of canonical Notch signalling in the keratinocyte UVB response

Anna Mandinova1, Karine Lefort, Alice Tommasi di Vignano

  • 1Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, USA.

The EMBO Journal
|April 5, 2008
PubMed

Insights

The Notch signalling pathway protects skin cells from UVB damage by preventing apoptosis. This pathway suppresses the pro-apoptotic gene FoxO3a, crucial for skin cell survival after UV exposure.

Area of Science:

  • Dermatology
  • Molecular Biology
  • Cellular Biology

Background:

  • Notch signalling is vital for skin homeostasis, keratinocyte differentiation, and tumor suppression.
  • The role of Notch signalling in the keratinocyte response to ultraviolet B (UVB) radiation, particularly its anti-apoptotic function, is investigated.
  • UVB exposure induces Notch1 expression and activity in a p53-dependent manner in primary keratinocytes and epidermis.

Purpose of the Study:

  • To elucidate the anti-apoptotic function of Notch signalling in keratinocytes following UVB exposure.
  • To identify the molecular mechanisms by which Notch signalling confers protection against UVB-induced apoptosis.
  • To investigate the role of FoxO3a in the context of Notch signalling and UVB response.

Main Methods:

  • Utilizing primary keratinocytes and intact epidermis from both mouse and human origins.
  • Employing gene deletion, pharmacological inhibition, and genetic suppression to modulate Notch signalling.
  • Analyzing UVB-induced apoptosis, cell cycle withdrawal, and NF-kappaB activation.
  • Investigating the transcriptional regulation of FoxO3a by the Notch/HERP pathway.

Main Results:

  • UVB exposure significantly induces Notch1 expression and activity in a p53-dependent manner.
  • Suppression of Notch signalling enhances the apoptotic response to UVB.
  • Notch activation protects keratinocytes against apoptosis via a mechanism independent of cell cycle withdrawal or NF-kappaB activation.
  • The Notch/HERP pathway directly and negatively regulates the transcription of the pro-apoptotic gene FoxO3a.

Conclusions:

  • The canonical Notch/HERP pathway acts as a critical anti-apoptotic mechanism in keratinocytes exposed to UVB.
  • This protective effect is mediated through the negative transcriptional control of FoxO3a expression.
  • Understanding this pathway is crucial for developing strategies to protect skin from UV-induced damage and potentially prevent skin cancers.

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