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Critical roles for Rictor/Sin1 complexes in interferon-dependent gene transcription and generation of

Surinder Kaur1, Barbara Kroczynska1, Bhumika Sharma1

  • 1Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611.

The Journal of Biological Chemistry
|January 29, 2014
PubMed

Insights

Rictor and Sin1 are crucial for type I interferon (IFN) signaling, impacting STAT activation and the expression of IFN-inducible genes. These proteins are essential for IFNα

Area of Science:

  • Immunology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Type I interferons (IFNs) are critical for immune responses and have anti-cancer properties.
  • STAT (Signal Transducer and Activator of Transcription) proteins are key mediators of IFN signaling.
  • mTOR complex 2 (mTORC2), a crucial cellular regulator, contains Rictor (Rapamycin-insensitive companion of mTOR) as a core component.

Purpose of the Study:

  • To investigate the role of Rictor and its associated protein Sin1 in type I IFN signaling.
  • To determine the impact of Rictor/Sin1 disruption on STAT activation and IFN-inducible gene expression.
  • To elucidate the function of Rictor/Sin1 in the anti-neoplastic effects of IFNα against myeloproliferative neoplasms.

Main Methods:

  • Targeted gene disruption and knockdown (transient/stable) of Rictor and Sin1 in cellular models.
  • Assessment of STAT protein activation using Western blotting and electrophoretic mobility shift assays (EMSAs).
  • Quantification of IFN-inducible gene expression via quantitative PCR (qPCR).
  • Evaluation of IFNα's suppressive effects on malignant erythroid precursors from myeloproliferative neoplasm patients.

Main Results:

  • Disruption of Rictor diminished type I IFN-induced STAT activation.
  • Knockdown of Rictor or Sin1 led to impaired STAT pathway activation and reduced STAT-DNA binding.
  • This resulted in decreased expression of key IFN-inducible genes.
  • Rictor and Sin1 were found to be essential for IFNα's suppressive effects on malignant erythroid precursors in myeloproliferative neoplasms.

Conclusions:

  • Rictor/Sin1 complexes play a critical role in mediating type I IFN signaling.
  • These complexes are essential for the anti-cancer activity of type I IFNs, particularly IFNα.
  • Targeting Rictor/Sin1 may offer novel therapeutic strategies for myeloproliferative neoplasms and other cancers.
Keywords:
Akt PKBAntiviral AgentsCell SignalingCytokines/InterferonGene RegulationInterferonSignal Transduction

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