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Experimental Approaches to Study Mitochondrial Localization and Function of a Nuclear Cell Cycle Kinase, Cdk1
13:15

Experimental Approaches to Study Mitochondrial Localization and Function of a Nuclear Cell Cycle Kinase, Cdk1

Published on: February 25, 2016

Heterogeneous nuclear ribonucleoprotein A1 regulates cyclin D1 and c-myc internal ribosome entry site function

Oak D Jo1, Jheralyn Martin, Andrew Bernath

  • 1Department of Research and Development, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 91343, USA.

The Journal of Biological Chemistry
|June 20, 2008
PubMed

Insights

Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) regulates cyclin D1 and c-myc mRNA translation via internal ribosome entry site (IRES) activity. Akt-mediated phosphorylation of hnRNP A1 controls this process, impacting cell cycle progression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Translation of cyclin D1 and c-myc mRNAs is regulated by internal ribosome entry site (IRES)-mediated initiation.
  • This process is influenced by reduced eIF-4F complex formation and Akt activity.

Purpose of the Study:

  • To identify the IRES trans-acting factor regulating cyclin D1 and c-myc IRES activity.
  • To elucidate the role of Akt in modulating this IRES activity.

Main Methods:

  • In vitro binding assays and reporter gene expression assays.
  • Analysis of hnRNP A1 phosphorylation and its effect on IRES activity.
  • Cellular knockdown and overexpression studies.
  • Monitoring mRNA polysome distribution.

Main Results:

  • hnRNP A1 identified as a key regulator of cyclin D1 and c-myc IRES activity, dependent on Akt status.
  • Akt phosphorylates hnRNP A1 at serine 199, inhibiting its ability to support IRES activity.
  • hnRNP A1 knockdown or inhibition of its function impairs rapamycin-stimulated IRES activity and alters mRNA polysome loading.
  • hnRNP A1 knockdown sensitizes cells to rapamycin-induced G1 arrest.

Conclusions:

  • hnRNP A1 mediates rapamycin-induced changes in cyclin D1 and c-myc IRES activity in an Akt-dependent manner.
  • Establishes a direct link between Akt signaling and the regulation of IRES activity.

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