Post-Transcriptional Regulation of the GAP-43 Gene by Specific Sequences in the 3′ Untranslated Region of the mRNA

Tsai, Kao-Chung; Cansino, Victor V.; Kohn, Douglas T.; Neve, Rachael L.; Perrone‐Bizzozero, Nora I.

doi:10.1523/jneurosci.17-06-01950.1997

Cited by 66 publications

(87 citation statements)

References 53 publications

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“…These regions often include a core sequence of ATnG, where n represents a variable repeat of Ϸ3-5 T (uridine) residues. The ATnG core sequence in the upstream elements may enhance efficiency of poly(A) signal usage and mRNA transcript stability of a number of genes (26)(27)(28). In addition, three copies of another motif, ATTTA, a mediator of mRNA destabilization (29), were identified in conserved regions of znf503.…”

Section: Discussionmentioning

confidence: 99%

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RNA expression in a cartilaginous fish cell line reveals ancient 3′ noncoding regions highly conserved in vertebrates

Forest

Nishikawa

Kobayashi

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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We have established a cartilaginous fish cell line [Squalus acanthias embryo cell line (SAE)], a mesenchymal stem cell line derived from the embryo of an elasmobranch, the spiny dogfish shark S. acanthias. Elasmobranchs (sharks and rays) first appeared >400 million years ago, and existing species provide useful models for comparative vertebrate cell biology, physiology, and genomics. Comparative vertebrate genomics among evolutionarily distant organisms can provide sequence conservation information that facilitates identification of critical coding and noncoding regions. Although these genomic analyses are informative, experimental verification of functions of genomic sequences depends heavily on cell culture approaches. Using ESTs defining mRNAs derived from the SAE cell line, we identified lengthy and highly conserved gene-specific nucleotide sequences in the noncoding 3 UTRs of eight genes involved in the regulation of cell growth and proliferation. Conserved noncoding 3 mRNA regions detected by using the shark nucleotide sequences as a starting point were found in a range of other vertebrate orders, including bony fish, birds, amphibians, and mammals. Nucleotide identity of shark and human in these regions was remarkably well conserved. Our results indicate that highly conserved gene sequences dating from the appearance of jawed vertebrates and representing potential cis-regulatory elements can be identified through the use of cartilaginous fish as a baseline. Because the expression of genes in the SAE cell line was prerequisite for their identification, this cartilaginous fish culture system also provides a physiologically valid tool to test functional hypotheses on the role of these ancient conserved sequences in comparative cell biology.noncoding sequence ͉ sequence conservation ͉ Squalus acanthias E fforts toward a comprehensive compilation of cell biological, physiological, and genomic information from a variety of vertebrate species are providing a rich source of comparative data representing critical points in evolutionary divergence (1). Although available information is rapidly expanding for teleosts (bony fishes; ref.2), few cell biological or genomic data are available for the most primitive jawed vertebrates, the cartilaginous fish, class Chondrichthyes, largely represented by the order Elasmobranchii (3, 4). This information would extend comparative data through Ͼ450 million years of evolution. We have derived an embryonic mesenchymal stem cell line [Squalus acanthias embryo cell line (SAE)] from the elasmobranch S. acanthias, the spiny dogfish shark (5). This cell line from a cartilaginous fish provides a means to study the cell biology, physiology, and genomics of Chondrichthyes. Recently, the National Human Genome Research Institute targeted for comprehensive genomic sequencing Leucoraja erinacia, an elasmobranch of the superorder Squaliformes, related to S. acanthias, underscoring the value of Chondrichthyes for comparative biology (6) In efforts to explore the cell biology and genomics of c...

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Section: Discussionmentioning

confidence: 99%

“…It has been reported that phylogenetic footprints in 3Ј UTRs are generally enriched in adenosine and uridine (7). Zinc-finger protein 503 (27) References given are recent examples of many. See Discussion for a brief statement of cellular function.…”

Section: Noncoding Regions Of Shark Ppp4r2 and Set Genes In Other Vermentioning

confidence: 99%

RNA expression in a cartilaginous fish cell line reveals ancient 3′ noncoding regions highly conserved in vertebrates

Forest

Nishikawa

Kobayashi

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…RNA decay assays were performed as previously described (Tsai et al, 1997). Briefly, cultures were treated with 5 M cadmium, which causes an 8-to 10-fold activation of the human metallothionein-IIA promoter in the pMEP4 vector.…”

Section: Gap-43 Mrna Stability Analysis In Transfected Cell Linesmentioning

confidence: 99%

“…For these studies, a GAP-43 deficient PC12 subclone, PC12-N36, was cotransfected with full length GAP-43 cDNA in the inducible expression vector pMEP4 (Kohn et al, 1996) and with either pDuH or pcDNA3. As in previous studies, cells were exposed for 16 h to 5 M cadmium to induce high levels of GAP-43 mRNA via activation of the metallothionein promoter in pMEP4 (Tsai et al, 1997). After induction, cadmium was removed and the RNA harvested at various time points.…”

Section: Molecular Biology Of the Cell 3194mentioning

confidence: 99%

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The RNA-binding Protein HuD Is Required for GAP-43 mRNA Stability, GAP-43 Gene Expression, and PKC-dependent Neurite Outgrowth in PC12 Cells

Mobarak¹,

Anderson²,

Morin³

et al. 2000

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146

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The RNA-binding protein HuD binds to a regulatory element in the 3Ј untranslated region (3Ј UTR) of the GAP-43 mRNA. To investigate the functional significance of this interaction, we generated PC12 cell lines in which HuD levels were controlled by transfection with either antisense (pDuH) or sense (pcHuD) constructs. pDuH-transfected cells contained reduced amounts of GAP-43 protein and mRNA, and these levels remained low even after nerve growth factor (NGF) stimulation, a treatment that is normally associated with protein kinase C (PKC)-dependent stabilization of the GAP-43 mRNA and neuronal differentiation. Analysis of GAP-43 mRNA stability demonstrated that the mRNA had a shorter half-life in these cells. In agreement with their deficient GAP-43 expression, pDuH cells failed to grow neurites in the presence of NGF or phorbol esters. These cells, however, exhibited normal neurite outgrowth when exposed to dibutyryl-cAMP, an agent that induces outgrowth independently from GAP-43. We observed opposite effects in pcHuD-transfected cells. The GAP-43 mRNA was stabilized in these cells, leading to an increase in the levels of the GAP-43 mRNA and protein. pcHuD cells were also found to grow short spontaneous neurites, a process that required the presence of GAP-43. In conclusion, our results suggest that HuD plays a critical role in PKC-mediated neurite outgrowth in PC12 cells and that this protein does so primarily by promoting the stabilization of the GAP-43 mRNA. INTRODUCTIONIn addition to transcriptional factors, RNA-binding proteins play a critical role in the developmental control of gene expression. Among these is ELAV (embryonic lethal abnormal vision), an RNA-binding protein identified in Drosophila, where the gene is required for normal development and maintenance of the nervous system (Campos et al., 1985;Robinow et al., 1988). In higher vertebrates and mammals, four members of the ELAV-like family have been identified. These are also referred to as Hu proteins, namely HuR (also known as HuA), HuB (Hel-N1), HuC, and HuD, because these are targets of anti-Hu antibodies present in the sera of patients with paraneoplastic encephalomyelitis (Dalmau et al., 1992). HuR is ubiquitously expressed (Ma et al., 1996), while HuB, HuC, and HuD are expressed uniquely in the nervous system. Recent studies indicate that overexpression of neural ELAV-like proteins is sufficient to induce neuronal differentiation in vitro and in vivo (Wakamatsu and Weston, 1997; Akamatsu et al., 1999;Antic et al., 1999;Kasashima et al., 1999). While the exact function and targets of ELAV/Hu proteins remain to be fully elucidated, it seems likely that this family of RNA-binding proteins controls neuronal differentiation by selectively modulating the expression of neural-specific, growth-associated genes.The growth-associated protein GAP-43 is expressed in neurons primarily during the initial establishment and regeneration of neural connections (Skene, 1989;Benowitz and Routtenberg, 1997 Eggen et al., 1995;Chiaramello et al., 1996;Kinney et ...

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Activity-dependent regulation of axonal growth: Posttranscriptional control of the GAP-43 gene by the NMDA receptor in developing hippocampus

Cantallops

Routtenberg

1999

J. Neurobiol.

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Post-Transcriptional Regulation of the GAP-43 Gene by Specific Sequences in the 3′ Untranslated Region of the mRNA

Cited by 66 publications

References 53 publications

RNA expression in a cartilaginous fish cell line reveals ancient 3′ noncoding regions highly conserved in vertebrates

RNA expression in a cartilaginous fish cell line reveals ancient 3′ noncoding regions highly conserved in vertebrates

The RNA-binding Protein HuD Is Required for GAP-43 mRNA Stability, GAP-43 Gene Expression, and PKC-dependent Neurite Outgrowth in PC12 Cells

Activity-dependent regulation of axonal growth: Posttranscriptional control of the GAP-43 gene by the NMDA receptor in developing hippocampus

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