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The Lats2 tumor suppressor augments p53-mediated apoptosis by promoting the nuclear proapoptotic function of ASPP1

Yael Aylon1, Yaara Ofir-Rosenfeld, Norikazu Yabuta

  • 1Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.

Genes & Development
|November 3, 2010
PubMed

Insights

The tumor suppressor Lats2 phosphorylates ASPP1, driving it into the nucleus to promote cancer cell death. Yap1 oncoprotein disrupts this axis, counteracting tumor suppression.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Biology

Background:

  • Apoptosis is crucial for eliminating pre-cancerous cells, with p53 as a key regulator.
  • Tumors can evade p53's tumor-suppressive functions by modifying proteins in the p53 pathway.
  • ASPP1 (apoptosis-stimulating protein of p53-1) mediates the nuclear p53 apoptotic response.

Purpose of the Study:

  • To investigate the role of Lats2 (large tumor suppressor 2) in regulating ASPP1 localization and function.
  • To elucidate the mechanism by which Lats2 and ASPP1 cooperate to induce apoptosis.
  • To understand how the Yap1 oncoprotein interferes with the Lats2/ASPP1/p53 tumor-suppressive axis.

Main Methods:

  • Investigated protein localization and phosphorylation in response to oncogenic stress.
  • Utilized biochemical assays to study protein-protein interactions.
  • Examined the effects of Lats2, ASPP1, and Yap1 on p53 localization and apoptotic promoter activity.

Main Results:

  • Lats2 phosphorylates cytoplasmic ASPP1, inducing its nuclear translocation under oncogenic stress.
  • The Lats2-ASPP1 complex directs p53 to proapoptotic promoters, leading to the death of polyploid cells.
  • Yap1 (Yes-associated protein 1) disrupts Lats2-ASPP1 binding, inhibiting their tumor-suppressive activity.

Conclusions:

  • Lats2-mediated nuclear translocation of ASPP1 is a critical step in initiating p53-dependent apoptosis.
  • The Lats2/ASPP1/p53 axis represents a novel tumor-suppressive pathway.
  • Yap1 antagonizes this pathway, highlighting its role in oncogenesis and potential as a therapeutic target.

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