Embryonic Lethal Abnormal Visual RNA-Binding Proteins Involved in Growth, Differentiation, and Posttranscriptional Gene Expression

Abstract

Cell growth and differentiation in mammalian tissues are regulated by tight control of gene expression at the transcriptional, posttranscriptional, and translational levels. Although transcription is the primary level of regulation of gene expression, it has become clear that several levels of posttranscriptional RNA processing play important roles in regulating the final outcome of protein production. Processing of eukaryotic pre-mRNA, including polyadenylation, capping, and splicing, as well as transport of RNAs, affect the availability of mature mRNA for translation. In addition, the localization, stability, and translatability of cytoplasmic mRNAs affect both quantitative and qualitative aspects of final gene expression. Although many genes have been shown to influence organismal development through transcriptional regulation, relatively few have been implicated in regulation of cell growth or differentiation at posttranscriptional levels. As might be expected, RNA-protein interactions play key regulatory roles in postranscriptional gene expression. One gene whose product acts at the level of RNA processing was discovered in a genetic screen of the fruit fly Drosophila melanogaster. This gene, named elav (pronounced ellavee) for the embryonic lethal abnormal visual phenotype, is essential for the development and maintenance of the

Post‐transcriptional regulation of gene expression by degradation of messenger RNAs

“…ELAV proteins are a family of RNAbinding proteins essential in Drosophila for neural development (Campos et al, 1985). 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 (Szabo et al, 1991;King et al, 1994;Good, 1995;Ma et al, 1996;Antic and Keene, 1997). HuR is the best-characterized ELAV protein Brennan and Steitz, 2001;Wilusz et al, 2001).…”

HuR in the Mammalian Genotoxic Response: Post-Transcriptional Multitasking

“…4 HuR is a ubiquitously expressed member of the Hu/ELAV (embryonic lethal abnormal vision in D. melanogaster) family of RNA-binding proteins, which also comprises the primarily neuronal proteins HuB, HuC, and HuD. [5][6][7][8][9] Hu proteins possess three RNA-recognition motifs through which they bind with high affinity and specificity to target mRNAs containing regions rich in adenines and uracils (AU-rich elements or AREs), and to regulate their stability (as shown for VEGF, p21, cyclin A, cyclin B1, c-fos), translation (as reported for p27, neurofilament N, GAP-43 and p53), or both (as reported for GLUT1). [10][11][12][13][14][15][16][17][18] Like other RNA-binding proteins, whose subcellular location often changes in response to stimulation, HuR cytoplasmic abundance increases in response to DNA damaging agents such as UVC and actinomycin D. 4 We have recently provided evidence in support of an additional level of post-transcriptional gene regulation by HuR in response to genotoxins.…”

Region-specific alternative splicing in the nervous system: Implications for regulation by the RNA-binding protein NAPOR

“…The polypyrimidine-tract-binding protein (PTB, also called hnRNP I) is a negative regulator of alternative splicing affecting multiple targets in the nervous system and muscle (Valcarcel & Gebauer, 1997)+ PTB has four RNA recognition motif type (RRM) RNA binding domains, and down-regulates neural exon selection by direct binding to intronic repressor elements in a variety of transcripts, including the c-src tyrosine kinase, GABA A receptor g2, Clathrin light chain B, and NMDA R1 receptor exon 5 (Grabowski & Black, 2001)+ The low levels of PTB expression in the mature rodent (Ashiya & Grabowski, 1997;Lillevali et al+, 2001) or human (Markovtsov et al+, 2000) brain are consistent with the idea that PTB represses neural-enriched splicing events in nonneural cells+ In addition, PTB is implicated in the coordinate regulation of some neuralenriched splicing events during cerebellum development, as its expression decreases with increasing postnatal age (Wang & Grabowski, 1996;Zhang et al+, 1999)+ The neural-enriched paralog of PTB, nPTB (also called brPTB), shows a complementary pattern of expression such that its expression increases with postnatal age (Markovtsov et al+, 2000;Polydorides et al+, 2000)+ Furthermore, nPTB interacts with Nova-1 in a yeast two-hybrid assay and counteracts the positive effects of Nova-1 on alternative splicing in transient coexpression assays (Polydorides et al+, 2000)+ KSRP (for KH-type splicing regulatory protein), is a neural-enriched RNA-binding protein identified from a neuronal splicing extract through its binding to the intronic enhancer of the c-src transcript, where it functions to promote the assembly of the intronic enhancer complex (Min et al+, 1997)+ HnRNPs F and H also associate with the intronic enhancer preferentially in a neural splicing extract, although the expression patterns of these proteins are not strongly tissue specific (Chou et al+, 1999)+ In Drosophila, the embryonic lethal abnormal vision (ELAV) RNA-binding protein, exhibits a neuron-specific expression pattern and is believed to play an important role in the regulation of alternative splicing of neuroglian (Koushika et al+, 1996)+ In mammals, the ELAVrelated Hu-type RNA-binding proteins HuB, HuC, and HuD have a neural-specific expression pattern, are predominantly cytoplasmic, and associate with a distinct subset of mRNAs (Keene, 2001)+ Their characterized functions involve the control of mRNA stability and translation (Antic & Keene, 1997;Lazarova et al+, 1999)+ Additionally, a distinct set of RNA-binding proteins, termed Musashi, is expressed in the precursors of mitotically active neurons+ Musashi proteins are implicated in translational control and pre-mRNA processing, although the detailed functions of these proteins are poorly understood (Nakamura et al+, 1994;Sakakibara et al+, 1996;Sakakibara & Okano, 1997)+…”