Abstract
The Elav-like proteins are specific mRNA-binding proteins that regulate mRNA stability. The neuronal members of this family (HuD, HuC, and Hel-N1) are required for neuronal differentiation. In this report, using purified HuD protein we have localized a high affinity HuD binding site to a 42-nucleotide region within a U-rich tract in the 3'-untranslated region p21(waf1) mRNA. The binding of HuD to this site is readily displaced by an RNA oligonucleotide encoding the HuD binding site of c-fos. The sequence of this binding site is well conserved in human, mouse, and rat p21(waf1) mRNA. p21(waf1) is an inhibitor of cyclin-dependent kinases and proliferating cell nuclear antigen and induces cell cycle arrest at G1/S, a requisite early step in cell differentiation. The identification of an Elav-like protein binding site in the 3'-untranslated region of p21(waf1) provides a novel link between the induction of differentiation, mRNA stability, and the termination of the cell cycle.
Highlights
The Elav-like proteins are tumor antigens that are the human homologues of the Drosophila protein Elav (1).There are four members of the human Elav-like family, namely HuD, HuC, Hel-N1, and HuR (1–5)
It is thought that HuD, HuC, and Hel-N1 are involved in neuronal differentiation, since they are expressed on termination of the neuroblast cell cycle (10 –12)
We have looked for new mRNAs targets that may directly affect the neuroblast cell cycle
Summary
The Elav-like proteins are tumor antigens that are the human homologues of the Drosophila protein Elav (1).There are four members of the human Elav-like family, namely HuD, HuC, Hel-N1, and HuR (1–5). It is thought that HuD, HuC, and Hel-N1 are involved in neuronal differentiation, since they are expressed on termination of the neuroblast cell cycle (10 –12). The Elav-like proteins bind to these elements, stabilize the mRNA, and thereby increase its steady state level. The Elav-like proteins are turned on very soon after the last S phase of the precursor neuroblast (6, 11) This event occurs before the documented changes in GAP-43 and tau expression. This suggested to us that the Elav-like proteins may regulate other mRNAs. In particular, we postulated that the Elav-like proteins may regulate mRNAs involved in the termination of the neuroblast cell cycle. P21waf may be the connection between the Elav-like proteins and the termination of the neuroblast cell cycle. In this paper we show that HuD binds to a conserved U-rich element within the 3Ј-UTR2 of p21waf mRNA
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