Coordinate regulation of mRNA decay networks by GU-rich elements and CELF1

Abstract

The GU-rich element (GRE) was identified as a conserved sequence enriched in the 3' UTR of human transcripts that exhibited rapid mRNA turnover. In mammalian cells, binding to GREs by the protein CELF1 coordinates mRNA decay of networks of transcripts involved in cell growth, migration, and apoptosis. Depending on the context, GREs and CELF1 also regulate pre-mRNA splicing and translation. GREs are highly conserved throughout evolution and play important roles in the development of organisms ranging from worms to man. In humans, abnormal GRE-mediated regulation contributes to disease states and cancer. Thus, GREs and CELF proteins serve critical functions in gene expression regulation and define an important evolutionarily conserved posttranscriptional regulatory network.

Figure 1. T-cell receptor signaling pathways regulated by GREs

The network diagram depicts the coordinate regulation of GRE-containing transcripts involved in T cell receptor signaling. Transcripts in bold are GRE-containing. Transcripts in grey were identified as CELF1 targets in HeLa cells by RNA-IP [43]. Transcripts in green represent short-lived GRE-containing transcripts expressed in primary human T cells [33], [37]. Transcripts labeled with an asterisk exhibited changes in steady state levels following T-cell receptor stimulation [33]. This network diagram was built using Ingenuity Pathway Assistant Software.

Figure 2. A posttranscriptional network of CELF1 target transcripts in mouse myoblasts

Transcripts shown in orange are CELF1 targets in mouse myoblasts [47]. Transcripts shown in red are CELF1 targets in mouse myoblasts and are also targets of EDEN-BP in Xenopus tropicalis extracts [48]. Transcripts, marked with asterisk (*), were stabilized in CELF1 knockout myoblasts. This network diagram was built using Ingenuity Pathway Assistant Software.

Figure 3. A posttranscriptional network of CELF1 target transcripts in malignant cells

This network represents transcripts that involved in G protein coupled receptor signaling pathways. Transcripts depicted in tan represent GRE-containing CELF1 target transcripts in HeLa cells [43]. This network diagram was built using Ingenuity Pathway Assistant Software.