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ΔNp63α represses nuclear translocation of PTEN by inhibition of NEDD4-1 in keratinocytes

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Abstract

ΔNp63α maintains the proliferative potential of keratinocytes by inhibiting the transcription and nuclear localization of the tumor suppressor PTEN as shown earlier by our laboratory. The goal of this study was to define the mechanisms by which ΔNp63α mediates the nuclear exclusion of PTEN. We demonstrate here that ΔNp63α reduces the ubiquitination of PTEN, a key signaling event in the nuclear translocation of PTEN. The decrease in ubiquitinated PTEN correlated with the ability of ΔNp63α to bind to neuronal precursor developmentally down regulated 4 (NEDD4) promoter and transcriptionally repress the E3 ubiquitin ligase NEDD4-1. Knockdown of NEDD4-1 in cultured keratinocytes was sufficient to attenuate the increase in nuclear PTEN observed upon silencing of ΔNp63α. In vivo examination of normal skin demonstrated that ΔNp63α and NEDD4-1 were both expressed in the basal layer of the epidermis and this correlated with nuclear exclusion of PTEN. Altogether, these studies suggest that ΔNp63α-mediated suppression of nuclear PTEN in basal layer keratinocytes occurs through repression of NEDD4-1.

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Acknowledgments

This work was supported by grant 1R01CA154715 from the National Institutes of Health.

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The authors declare no conflicts of interests.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, 122 Diggs Laboratory, 3640 Colonel Glenn Highway, Dayton, OH, 45435, USA

    Mary K. Leonard, Natasha T. Hill, Ethan D. Grant & Madhavi P. Kadakia

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  1. Mary K. Leonard
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  2. Natasha T. Hill
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  3. Ethan D. Grant
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  4. Madhavi P. Kadakia
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Corresponding author

Correspondence to Madhavi P. Kadakia.

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M. K. Leonard and N. Hill contributed equally to the paper.

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Leonard, M.K., Hill, N.T., Grant, E.D. et al. ΔNp63α represses nuclear translocation of PTEN by inhibition of NEDD4-1 in keratinocytes. Arch Dermatol Res 305, 733–739 (2013). https://doi.org/10.1007/s00403-013-1352-7

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  • DOI: https://doi.org/10.1007/s00403-013-1352-7

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