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Oncogenic Wip1 phosphatase is inhibited by miR-16 in the DNA damage signaling pathway

Xinna Zhang1, Guohui Wan, Sizolwenkosi Mlotshwa

  • 1Department of Biological Sciences and Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA.

Cancer Research
|July 30, 2010
PubMed

Insights

MicroRNA-16 (miR-16) regulates Wild-type p53-induced phosphatase 1 (Wip1) expression, impacting DNA damage response and mammary tumorigenesis. Downregulation of miR-16 in cancer stem cells promotes tumor growth and chemoresistance.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Wild-type p53-induced phosphatase 1 (Wip1) is an oncogene overexpressed in cancers, inhibiting ATM/ATR-p53 DNA damage signaling.
  • Wip1 dephosphorylates DNA damage proteins, reversing cell cycle checkpoints and is transcriptionally induced by p53.

Purpose of the Study:

  • To investigate the temporal and functional regulation of Wip1.
  • To identify regulatory mechanisms of Wip1 in DNA damage response and mammary tumorigenesis.

Main Methods:

  • Identification of microRNA-16 (miR-16) as a negative regulator of Wip1 mRNA.
  • Analysis of miR-16 induction kinetics post-DNA damage.
  • Examination of miR-16 expression in mammary tumor stem cells.
  • Assessment of miR-16 or Wip1 inhibition effects on mammary tumor stem cell self-renewal and growth.
  • Evaluation of miR-16 effects on breast cancer cell chemosensitivity.

Main Results:

  • miR-16 directly targets and downregulates Wip1 expression.
  • miR-16 is induced immediately after DNA damage, delaying Wip1 protein increase and ensuring functional DNA damage response.
  • miR-16 is downregulated in mammary tumor stem cells.
  • Overexpression of miR-16 or Wip1 inhibition suppressed mammary tumor stem cell growth and enhanced chemosensitivity.

Conclusions:

  • miR-16 plays a crucial role in regulating Wip1 phosphatase during DNA damage response.
  • Dysregulation of the miR-16/Wip1 axis contributes to mammary tumorigenesis and chemoresistance.

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