Loss of endogenous Nfatc1 reduces the rate of DMBA/TPA-induced skin tumorigenesis

Jill Goldstein, Eve Roth, Natalie Roberts, Rachel Zwick, Samantha Lin, Sean Fletcher, Ana Tadeu, Christine Wu, Amanda P. Beck, Caroline Zeiss, Mayte Suárez-Fariñas, Valerie Horsley

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Immunosuppressive therapies using calcineurin inhibitors, such as cyclosporine A, are associated with a higher incidence of squamous cell carcinoma formation in mice and humans. Calcineurin is believed to suppress tumorigenesis in part through Nfatc1, a transcription factor expressed primarily in hair follicle bulge stem cells in mice. However, mice overexpressing a constitutively active Nfatc1 isoform in the skin epithelium developed increased spontaneous skin squamous cell carcinomas. Because follicular stem cells can contribute to skin tumorigenesis, whether the endogenous expression of Nfatc1 inhibits or enhances skin tumorigenesis is unclear. Here we show that loss of the endogenous expression of Nfatc1 suppresses the rate of DMBA/TPA-induced skin tumorigenesis. Inducible deletion of Nfatc1 in follicular stem cells before tumor initiation significantly reduces the rate of tumorigenesis and the contribution of follicular stem cells to skin tumors. We find that skin tumors from mice lacking Nfatc1 display reduced Hras codon 61 mutations. Furthermore, Nfatc1 enhances the expression of genes involved in DMBA metabolism and increases DMBA-induced DNA damage in keratinocytes. Together these data implicate Nfatc1 in the regulation of skin stem cell-initiated tumorigenesis via the regulation of DMBA metabolism.

Original languageEnglish (US)
Pages (from-to)3606-3614
Number of pages9
JournalMolecular Biology of the Cell
Volume26
Issue number20
DOIs
StatePublished - Oct 15 2015
Externally publishedYes

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9,10-Dimethyl-1,2-benzanthracene
Carcinogenesis
Skin
Stem Cells
Squamous Cell Carcinoma
Neoplastic Stem Cells
Hair Follicle
Calcineurin
Immunosuppressive Agents
Keratinocytes
Codon
Cyclosporine
DNA Damage
Neoplasms
Protein Isoforms
Transcription Factors
Epithelium
Gene Expression
Mutation
Incidence

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Goldstein, J., Roth, E., Roberts, N., Zwick, R., Lin, S., Fletcher, S., ... Horsley, V. (2015). Loss of endogenous Nfatc1 reduces the rate of DMBA/TPA-induced skin tumorigenesis. Molecular Biology of the Cell, 26(20), 3606-3614. https://doi.org/10.1091/mbc.E15-05-0282

Loss of endogenous Nfatc1 reduces the rate of DMBA/TPA-induced skin tumorigenesis. / Goldstein, Jill; Roth, Eve; Roberts, Natalie; Zwick, Rachel; Lin, Samantha; Fletcher, Sean; Tadeu, Ana; Wu, Christine; Beck, Amanda P.; Zeiss, Caroline; Suárez-Fariñas, Mayte; Horsley, Valerie.

In: Molecular Biology of the Cell, Vol. 26, No. 20, 15.10.2015, p. 3606-3614.

Research output: Contribution to journalArticle

Goldstein, J, Roth, E, Roberts, N, Zwick, R, Lin, S, Fletcher, S, Tadeu, A, Wu, C, Beck, AP, Zeiss, C, Suárez-Fariñas, M & Horsley, V 2015, 'Loss of endogenous Nfatc1 reduces the rate of DMBA/TPA-induced skin tumorigenesis', Molecular Biology of the Cell, vol. 26, no. 20, pp. 3606-3614. https://doi.org/10.1091/mbc.E15-05-0282
Goldstein J, Roth E, Roberts N, Zwick R, Lin S, Fletcher S et al. Loss of endogenous Nfatc1 reduces the rate of DMBA/TPA-induced skin tumorigenesis. Molecular Biology of the Cell. 2015 Oct 15;26(20):3606-3614. https://doi.org/10.1091/mbc.E15-05-0282
Goldstein, Jill ; Roth, Eve ; Roberts, Natalie ; Zwick, Rachel ; Lin, Samantha ; Fletcher, Sean ; Tadeu, Ana ; Wu, Christine ; Beck, Amanda P. ; Zeiss, Caroline ; Suárez-Fariñas, Mayte ; Horsley, Valerie. / Loss of endogenous Nfatc1 reduces the rate of DMBA/TPA-induced skin tumorigenesis. In: Molecular Biology of the Cell. 2015 ; Vol. 26, No. 20. pp. 3606-3614.
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