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Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
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Cytoplasmic PML function in TGF-beta signalling.

Hui-Kuan Lin1, Stephan Bergmann, Pier Paolo Pandolfi

  • 1Cancer Biology and Genetics Program, Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, New York, 10021, USA.

Nature
|September 10, 2004
PubMed
Summary
This summary is machine-generated.

Cytoplasmic promyelocytic leukaemia (PML) protein regulates transforming growth factor beta (TGF-beta) signaling. PML is essential for TGF-beta-induced growth arrest and apoptosis, with its absence impairing Smad protein function.

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Published on: September 14, 2021

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Transforming growth factor beta (TGF-beta) is a key tumor suppressor, but cancer cells often evade its effects.
  • Promyelocytic leukaemia (PML) protein, known as a tumor suppressor, has nuclear and cytoplasmic isoforms with distinct functions.
  • The role of cytoplasmic PML in TGF-beta signaling remained largely unknown.

Purpose of the Study:

  • To investigate the function of cytoplasmic PML in TGF-beta signaling pathways.
  • To determine if cytoplasmic PML modulates TGF-beta-induced cellular responses.
  • To elucidate the molecular mechanism by which PML interacts with TGF-beta signaling components.

Main Methods:

  • Utilized Pml-null primary cells to assess TGF-beta response.
  • Analyzed phosphorylation and nuclear translocation of Smad2 and Smad3 proteins.
  • Investigated physical interactions between PML, Smad2/3, SARA, and TGF-beta receptors using co-immunoprecipitation and cellular localization studies.

Main Results:

  • Pml-null cells exhibited resistance to TGF-beta-mediated growth arrest, senescence, and apoptosis.
  • Impaired phosphorylation and nuclear translocation of Smad2/3 were observed in Pml-null cells.
  • Cytoplasmic PML physically interacts with Smad2/3 and SARA, facilitating Smad2/3-SARA complex formation and receptor accumulation in early endosomes.
  • TGF-beta treatment induced cytoplasmic PML expression.
  • PML-RARalpha oncoprotein antagonized cytoplasmic PML function, mirroring TGF-beta signaling defects in APL cells.

Conclusions:

  • Cytoplasmic PML is a critical regulator of TGF-beta signaling, essential for mediating its tumor suppressive functions.
  • PML's interaction with Smad proteins and receptor trafficking is crucial for effective TGF-beta pathway activation.
  • Dysregulation of cytoplasmic PML and TGF-beta signaling contributes to cancer pathogenesis, particularly in APL.