Oncogenic potential of TAR RNA binding protein TRBP and its regulatory interaction with RNA-dependent protein kinase PKR.
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.
Benkirane
M
M
Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD 20892-0460, USA.
Neuveut
C
C
Chun
R F
RF
Smith
S M
SM
Samuel
C E
CE
Gatignol
A
A
Jeang
K T
KT
D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D015497:HIV-1 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000235:genetics / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism* / Q000494:pharmacology; D014170:Transformation, Genetic / Q000235:genetics; D019892:eIF-2 Kinase; D000099253:Trans-Activation Responsive RNA-Binding Protein
D016898:Interferon-alpha; D017346:Protein Serine-Threonine Kinases; D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; D019892:eIF-2 Kinase; D000099253:Trans-Activation Responsive RNA-Binding Protein