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Oncogenic potential of TAR RNA binding protein TRBP and its regulatory interaction with RNA-dependent protein kinase
M Benkirane1, C Neuveut, R F Chun
1Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD 20892-0460, USA.
Abstract:
TAR RNA binding protein (TRBP) belongs to an RNA binding protein family that includes the double-stranded RNA-activated protein kinase (PKR), Drosophila Staufen and Xenopus xlrbpa. One member of this family, PKR, is a serine/threonine kinase which has anti-viral and anti-proliferative effects. In this study we show that TRBP is a cellular down-regulator of PKR function. Assaying expression from an infectious HIV-1 molecular clone, we found that PKR inhibited viral protein synthesis and that over-expression of TRBP effectively countered this inhibition. In intracellular and in cell-free assays we show that TRBP directly inhibits PKR autophosphorylation through an RNA binding-independent pathway. Biologically, TRBP serves a growth-promoting role; cells that overexpress TRBP exhibit transformed phenotypes. Our results demonstrate the oncogenic potential of TRBP and are consistent with the notion that intracellular PKR function contributes physiologically towards regulating cellular proliferation.
Insights
TAR RNA binding protein (TRBP) inhibits PKR, a protein kinase with anti-viral effects. TRBP promotes cell growth and exhibits oncogenic potential, regulating cellular proliferation.
Area of Science:
- Molecular Biology
- Virology
- Oncology
Background:
- TAR RNA binding protein (TRBP) is part of a protein family including double-stranded RNA-activated protein kinase (PKR).
- PKR is a serine/threonine kinase known for its anti-viral and anti-proliferative functions.
Purpose of the Study:
- To investigate the role of TRBP as a regulator of PKR.
- To determine the impact of TRBP on viral protein synthesis and cellular proliferation.
Main Methods:
- Assaying expression from an infectious HIV-1 molecular clone.
- Performing intracellular and cell-free assays to study TRBP-PKR interactions.
- Analyzing the effect of TRBP overexpression on cellular phenotypes.
Main Results:
- TRBP acts as a cellular down-regulator of PKR function.
- Overexpression of TRBP countered PKR's inhibition of viral protein synthesis.
- TRBP directly inhibits PKR autophosphorylation via an RNA binding-independent pathway.
- TRBP overexpression in cells led to transformed phenotypes, indicating a growth-promoting role.
Conclusions:
- TRBP demonstrates oncogenic potential.
- Intracellular PKR function is physiologically involved in regulating cellular proliferation.
- TRBP's regulation of PKR impacts both viral replication and cell growth.