Notch1 functions as a tumor suppressor in mouse skin

Abstract

Notch proteins are important in binary cell-fate decisions and inhibiting differentiation in many developmental systems, and aberrant Notch signaling is associated with tumorigenesis. The role of Notch signaling in mammalian skin is less well characterized and is mainly based on in vitro studies, which suggest that Notch signaling induces differentiation in mammalian skin. Conventional gene targeting is not applicable to establishing the role of Notch receptors or ligands in the skin because Notch1-/- embryos die during gestation. Therefore, we used a tissue-specific inducible gene-targeting approach to study the physiological role of the Notch1 receptor in the mouse epidermis and the corneal epithelium of adult mice. Unexpectedly, ablation of Notch1 results in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis. Notch1 deficiency in skin and in primary keratinocytes results in increased and sustained expression of Gli2, causing the development of basal-cell carcinoma-like tumors. Furthermore, Notch1 inactivation in the epidermis results in derepressed beta-catenin signaling in cells that should normally undergo differentiation. Enhanced beta-catenin signaling can be reversed by re-introduction of a dominant active form of the Notch1 receptor. This leads to a reduction in the signaling-competent pool of beta-catenin, indicating that Notch1 can inhibit beta-catenin-mediated signaling. Our results indicate that Notch1 functions as a tumor-suppressor gene in mammalian skin.

Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells

“…The consequences of such dysregulation does however seem to be highly cell type specific. For example, the constitutively activated form of Notch acts as a bona fide oncogene in leukaemia and in murine breast cancer, while recent data show that Notch-1 can function as a tumour suppressor gene in skin cancer (Ellisen et al, 1991;Uyttendaele et al, 1996;Nicolas et al, 2003). It has been suggested that these disparate effects might be dependent of the normal function of the cascade, that is, in tissues were Notch signalling is active in progenitor cells followed by a decreased signalling in differentiated cells, a constitutive activation of the cascade might lead to blocked differentiation or increased survival and proliferation (Allenspach et al, 2002).…”

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

“…Furthermore, the keratinocyte‐specific ablation of NOTCH1 induced significant proliferation of the basal epidermal layer and deregulated expressions of multiple differentiation markers, indicating disrupted balance between growth and differentiation 29. In a later research using similar conditional gene deletion technology, effects of long‐term NOTCH1 deficiency were further characterized 30. The induced Notch1 ‐/‐ adult mice showed epidermal hyperplasia followed by formation of skin tumors.…”

“…In the epidermis of induced Notch1 ‐/‐ mice, significantly high levels of free (unphosphorylated) beta‐catenin were observed 30. Loss of Notch1 signaling seems to activate beta‐catenin signaling in human CSCC 28, which can be repressed by the introduction of a dominant active form of NOTCH130.…”

“…The disruption of canonical Notch/CSL/MAML‐mediated signaling pathways in transgenic mice by expressing epidermal DNMAML1 (a pan‐Notch inhibitor) resulted in hyperplastic epidermis and spontaneously developed CSCC 28. In mouse keratinocytes, cyclin‐dependent kinase inhibitor p21 was identified as a downstream positive target of NOTCH1, where activated NOTCH1 induces p21 expression to suppress growth in a CSL‐dependent manner 29, 30. p21's role in tumor suppression was earlier investigated where p21 knockout keratinocytes exhibited significant downmodulation of differentiation markers and dramatic increase in proliferative potential 32.…”

“…In the epidermis of induced Notch1 ‐/‐ mice, significantly high levels of free (unphosphorylated) beta‐catenin were observed 30. Loss of Notch1 signaling seems to activate beta‐catenin signaling in human CSCC 28, which can be repressed by the introduction of a dominant active form of NOTCH130. In particular, p21 (a downstream mediator of Notch1‐induced growth arrest as we described above) also contributes to the downregulation of Wnt signaling, which likely account for the decreased levels of beta‐catenin activation by activated NOTCH134.…”