Post-transcriptional regulation of gene expression involves multiple checkpoints at which decisions are made concerning the fate of each messenger RNA species. Primary transcripts assemble into multicomponent ribonucleoprotein complexes during premRNA processing in the spliceosome, are transported out of the nucleus, and are either stored, degraded, or translated in the cytoplasm (1). Determining the outcome of this process for each individual mRNA species is complicated by the heterogeneity of the messenger ribonucleoprotein (mRNP) population, which contains various-size transcripts and diverse combinations of attached proteins. Although investigators have not yet devised methods to separate and characterize distinct cellular mRNPs, nature appears to distinguish each mRNP by using inherent signals in the RNAs and/or in the proteins in the mRNP complexes and tracking each mRNA to an appropriate functional outcome. For example, mRNAs may contain recognition sequences that can serve as ‘‘zip codes’’for tracking or localization (2) whereas in other cases, proteins attached to the mRNPs contain localization signals that allow their movement out of, or into, the nucleus (reviewed in ref. 3). In a previous issue of the Proceedings, Fan and Steitz (4) define a novel nuclear shuttling sequence in the Hu RNA-binding protein HuR, which may transport a specific subset of cellular mRNAs containing AU-rich elements (ARE) from the nucleus to the cytoplasm (Fig. 1). They term this signal the ‘‘HNS’’for HuR nuclear-cytoplasmic shuttling sequence because it contains both nuclear export and nuclear localization elements. This is particularly interesting because the ARE-containing mRNAs encode a functionally important subset of early-response gene (ERG) or immediateearly gene products, including protooncoproteins and cytokines. HuR (also called HuA) is one of four members of a family of human proteins that are highly homologous to a Drosophila nuclear protein known as ELAV (pronounced ‘‘e-la-vee’’), for embryonic lethal abnormal vision. Deletion mutants of the elav gene are embryonic-lethal because of abnormal development of neurons (5, 6). Temperature-sensitive mutations result in abnormal neuronal differentiation, which is most apparent in defects in the formation of Drosophila eyes. In mammals and in Xenopus, the Hu family consists of three members that are developmentally regulated and tissue-specific [Hel-N1 (also called HuB), HuC, and HuD], and one (HuR) that is ubiquitously expressed in all cell types (7–11). The mammalian ELAV/Hu cDNA encoding Hel-N1 (10) and all four Xenopus ELAV cDNAs (7) were cloned by using degenerate PCR based on Drosophila ELAV sequences whereas HuR was derived by degenerate PCR based on HuD cDNA sequences (8, 11). The mammalian HuC and HuD cDNAs were derived by screening a cDNA expression library with Hu autoimmune serum (11). The autoimmune serum used for the expression-cloning of HuD came from a patient with a paraneoplastic neurological disorder (PND)(12–14). PND patients have certain types of cancers, predominantly small cell lung carcinoma, and, in other cases, breast, ovarian, or prostate cancer. During the course of their disease, they develop autoantibodies against proteins ectopically expressed in the tumors (12). The humoral and cellular responses are mounted against these tumor proteins because they are normally expressed in an immune privileged site such as the central nervous system. In the case of the ELAV/Hu proteins, the small cell lung tumor expresses a tissue-specific Hu antigen: Hel-N1, HuC, or HuD. The antibodies made …