Multi-talented DEAD-box proteins and potential tumor promoters: p68 RNA helicase (DDX5) and its paralog, p72 RNA helicase (DDX17)

Abstract

P68 (DDX5) and p72 (DDX17) are members of the DEAD-box RNA helicase family. They can unwind double-stranded RNA and also contribute to the remodeling of ribonucleoprotein complexes. These activities of p68/p72 are required for efficient RNA splicing and microRNA processing. In addition, p68/p72 perform functions that are independent of their enzymatic activity. This is especially common to their role in gene regulation, where p68/p72 coactivate various transcription factors, including the tumor suppressor p53, estrogen receptor alpha and beta-catenin. P68/p72 are posttranslationally modified by SUMO attachment and phosphorylation that regulate their coactivation potential, binding to known interactants or protein stability. Knock-out mouse models revealed that both DDX5 and DDX17 are essential genes during development. Furthermore, together with their ability to stimulate cell proliferation and prevent apoptosis, the reported overexpression of p68/p72 in three of the major human cancers (colon, breast, prostate) strongly suggests that p68/p72 promote tumorigenesis and might even represent proto-oncoproteins. If so, their inhibition holds promise as a novel way to contain or cure various carcinomas.

Keywords: Cancer; DDX17; DDX5; DEAD-box; p68 RNA helicase; p72 RNA helicase.

Figure 1

Protein sequence alignment of p68 RNA helicase (DDX5) with DDX17. The 729 amino acid long DDX17 protein corresponds to p82 RNA helicase, whereas DDX17 amino acids 80-729 represent p72 RNA helicase. DDX5 amino acids were derived from NCBI reference sequence NP_004387.1 and DDX17 amino acids from NP_006377.2. Identical amino acids are highlighted by “+” and similar ones by “*”. Nine motifs characteristic for DEAD-box RNA helicases are boxed in red, as is the conserved phenylalanine preceding the Q-motif. Motifs I and II are also known as Walker A and B motifs, respectively. The center of motif II consists of the amino acid sequence Asp-Glu -Ala-Asp, after which the DEAD-box family of RNA helicases is named. Sumoylation and tyrosine phosphorylation sites are highlighted in green and yellow, respectively, and the IQ motif in orange.

Figure 2

Human multiple tissue Northern blot containing equal amounts of poly(A)⁺-RNA in each lane was hybridized with a human DDX5 cDNA probe. Arrows point to major DDX5 mRNAs of 4.2 and 2.4 kb size.

Figure 3

Reported sumoylation and phosphorylation sites in p68, p72 or p82 RNA helicase