Δnp63α regulates keratinocyte proliferation by controlling PTEN expression and localization

M. K. Leonard, R. Kommagani, V. Payal, Lindsey Mayo, H. N. Shamma, M. P. Kadakia

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

ΔNp63α, implicated as an oncogene, is upregulated by activated Akt, part of a well-known cell survival pathway. Inhibition of Akt activation by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and the presence of putative p63-binding sites in the pten promoter led us to investigate whether ΔNp63α regulates PTEN expression. Knockdown of ΔNp63α led to increases in PTEN levels and loss of activated Akt, while overexpression of ΔNp63α decreased PTEN levels and elevated active Akt. The repression of PTEN by ΔNp63α occurs independently of p53 status, as loss of ΔNp63α increases PTEN expression in cell lines with and without functional p53. In addition, decreased levels of ΔNp63α resulted in an increase in nuclear PTEN. Conversely, in vivo nuclear PTEN was absent in the proliferative basal layer of the epidermis where ΔNp63α expression is highest. Additionally, we show that in keratinocytes a balance between ΔNp63α and PTEN regulates Akt activation and maintains normal proliferation rates. This balance is disrupted in non-melanoma skin cancers through increased ΔNp63α levels, and could enhance proliferation and subsequent neoplastic development. Our studies show that ΔNp63α negatively regulates PTEN, thereby providing a feedback loop between PTEN, Akt and ΔNp63α, which has an integral role in skin cancer development.

Original languageEnglish
Pages (from-to)1924-1933
Number of pages10
JournalCell Death and Differentiation
Volume18
Issue number12
DOIs
StatePublished - Dec 2011

Fingerprint

Skin Neoplasms
Keratinocytes
Chromosomes, Human, Pair 10
Oncogenes
Phosphoric Monoester Hydrolases
Epidermis
Cell Survival
Binding Sites
Cell Line
Tensins

Keywords

  • Akt
  • keratinocytes
  • p63
  • PTEN
  • skin cancer

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Δnp63α regulates keratinocyte proliferation by controlling PTEN expression and localization. / Leonard, M. K.; Kommagani, R.; Payal, V.; Mayo, Lindsey; Shamma, H. N.; Kadakia, M. P.

In: Cell Death and Differentiation, Vol. 18, No. 12, 12.2011, p. 1924-1933.

Research output: Contribution to journalArticle

Leonard, M. K. ; Kommagani, R. ; Payal, V. ; Mayo, Lindsey ; Shamma, H. N. ; Kadakia, M. P. / Δnp63α regulates keratinocyte proliferation by controlling PTEN expression and localization. In: Cell Death and Differentiation. 2011 ; Vol. 18, No. 12. pp. 1924-1933.
@article{bce4a61ac3db4e19a84fac56fdf681d8,
title = "Δnp63α regulates keratinocyte proliferation by controlling PTEN expression and localization",
abstract = "ΔNp63α, implicated as an oncogene, is upregulated by activated Akt, part of a well-known cell survival pathway. Inhibition of Akt activation by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and the presence of putative p63-binding sites in the pten promoter led us to investigate whether ΔNp63α regulates PTEN expression. Knockdown of ΔNp63α led to increases in PTEN levels and loss of activated Akt, while overexpression of ΔNp63α decreased PTEN levels and elevated active Akt. The repression of PTEN by ΔNp63α occurs independently of p53 status, as loss of ΔNp63α increases PTEN expression in cell lines with and without functional p53. In addition, decreased levels of ΔNp63α resulted in an increase in nuclear PTEN. Conversely, in vivo nuclear PTEN was absent in the proliferative basal layer of the epidermis where ΔNp63α expression is highest. Additionally, we show that in keratinocytes a balance between ΔNp63α and PTEN regulates Akt activation and maintains normal proliferation rates. This balance is disrupted in non-melanoma skin cancers through increased ΔNp63α levels, and could enhance proliferation and subsequent neoplastic development. Our studies show that ΔNp63α negatively regulates PTEN, thereby providing a feedback loop between PTEN, Akt and ΔNp63α, which has an integral role in skin cancer development.",
keywords = "Akt, keratinocytes, p63, PTEN, skin cancer",
author = "Leonard, {M. K.} and R. Kommagani and V. Payal and Lindsey Mayo and Shamma, {H. N.} and Kadakia, {M. P.}",
year = "2011",
month = "12",
doi = "10.1038/cdd.2011.73",
language = "English",
volume = "18",
pages = "1924--1933",
journal = "Cell Death and Differentiation",
issn = "1350-9047",
publisher = "Nature Publishing Group",
number = "12",

}

TY - JOUR

T1 - Δnp63α regulates keratinocyte proliferation by controlling PTEN expression and localization

AU - Leonard, M. K.

AU - Kommagani, R.

AU - Payal, V.

AU - Mayo, Lindsey

AU - Shamma, H. N.

AU - Kadakia, M. P.

PY - 2011/12

Y1 - 2011/12

N2 - ΔNp63α, implicated as an oncogene, is upregulated by activated Akt, part of a well-known cell survival pathway. Inhibition of Akt activation by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and the presence of putative p63-binding sites in the pten promoter led us to investigate whether ΔNp63α regulates PTEN expression. Knockdown of ΔNp63α led to increases in PTEN levels and loss of activated Akt, while overexpression of ΔNp63α decreased PTEN levels and elevated active Akt. The repression of PTEN by ΔNp63α occurs independently of p53 status, as loss of ΔNp63α increases PTEN expression in cell lines with and without functional p53. In addition, decreased levels of ΔNp63α resulted in an increase in nuclear PTEN. Conversely, in vivo nuclear PTEN was absent in the proliferative basal layer of the epidermis where ΔNp63α expression is highest. Additionally, we show that in keratinocytes a balance between ΔNp63α and PTEN regulates Akt activation and maintains normal proliferation rates. This balance is disrupted in non-melanoma skin cancers through increased ΔNp63α levels, and could enhance proliferation and subsequent neoplastic development. Our studies show that ΔNp63α negatively regulates PTEN, thereby providing a feedback loop between PTEN, Akt and ΔNp63α, which has an integral role in skin cancer development.

AB - ΔNp63α, implicated as an oncogene, is upregulated by activated Akt, part of a well-known cell survival pathway. Inhibition of Akt activation by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and the presence of putative p63-binding sites in the pten promoter led us to investigate whether ΔNp63α regulates PTEN expression. Knockdown of ΔNp63α led to increases in PTEN levels and loss of activated Akt, while overexpression of ΔNp63α decreased PTEN levels and elevated active Akt. The repression of PTEN by ΔNp63α occurs independently of p53 status, as loss of ΔNp63α increases PTEN expression in cell lines with and without functional p53. In addition, decreased levels of ΔNp63α resulted in an increase in nuclear PTEN. Conversely, in vivo nuclear PTEN was absent in the proliferative basal layer of the epidermis where ΔNp63α expression is highest. Additionally, we show that in keratinocytes a balance between ΔNp63α and PTEN regulates Akt activation and maintains normal proliferation rates. This balance is disrupted in non-melanoma skin cancers through increased ΔNp63α levels, and could enhance proliferation and subsequent neoplastic development. Our studies show that ΔNp63α negatively regulates PTEN, thereby providing a feedback loop between PTEN, Akt and ΔNp63α, which has an integral role in skin cancer development.

KW - Akt

KW - keratinocytes

KW - p63

KW - PTEN

KW - skin cancer

UR - http://www.scopus.com/inward/record.url?scp=81155137696&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81155137696&partnerID=8YFLogxK

U2 - 10.1038/cdd.2011.73

DO - 10.1038/cdd.2011.73

M3 - Article

C2 - 21637289

AN - SCOPUS:81155137696

VL - 18

SP - 1924

EP - 1933

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

SN - 1350-9047

IS - 12

ER -