Alternative titles; symbols
HGNC Approved Gene Symbol: HNRNPD
Cytogenetic location: 4q21.22 Genomic coordinates (GRCh38): 4:82,352,498-82,373,991 (from NCBI)
The cytoplasmic instability of certain mRNAs is a critical regulatory component of gene expression. The mRNAs encoded by many genes important for controlling cell growth are very unstable, having half-lives on the order of 15 to 40 minutes. Mutations that stabilize certain mRNAs, such as FOS (164810) and MYC (190080), can contribute to oncogenic transformation. One class of cis-acting instability determinants is composed of AU-rich elements (AREs) found within the 3-prime untranslated regions of many protooncogenes and cytokine mRNAs (summarized by Wagner et al., 1996).
Brewer (1991) and Zhang et al. (1993) described the purification and characterization of AUF1, a potential mediator of ARE-directed mRNA degradation. AUF1 binds with high affinity to RNA molecules that contain ARE sequences from MYC, FOS, and GMCSF (138960) mRNAs. By contrast, AUF1 does not bind with high affinity to RNA sequences that lack an ARE. AUF1 is composed of at least 2 immunologically cross-reactive polypeptides with apparent molecular masses of 37 and 40 kD.
Zhang et al. (1993) used purified AUF1 protein to make polyclonal anti-AUF1 antibodies. They screened a HeLa cell expression library and isolated a clone (designated p37AUF1) that bound to AREs when tested. The 2.5-kb cDNA contains an ORF of 861 bp and produced a 37-kD in vitro translation product that comigrated with the p37AUF1 polypeptide. Sequence analysis revealed 2 nonidentical RNA recognition motifs (RRMs), a glutamine-rich region, and 3 putative phosphorylation sites. Metabolic labeling experiments showed that the translated protein is phosphorylated in K562 cells. Biochemical fractionation and immunofluorescence data suggested to Zhang et al. (1993) that AUF1 protein localizes to both the nucleus and the cytoplasm. Based on its homology to other RRM-containing proteins in GenBank, Zhang et al. (1993) speculated that p37AUF1 is part of a family of related proteins distinct from the hnRNP proteins, which includes the DL4 protein, the human homolog of lambda C6, and the human hnRNP A/B-like protein (see 600124). Wagner et al. (1996) noted that the RRMs of p37AUF1 are highly homologous with those of murine AUF1 (98% identity) and those of the Drosophila melanogaster 'Squid' gene product (43% identity), suggesting conserved functions. Wagner et al. (1996) cloned cDNAs encoding the AUF1 family of ARE-binding proteins from human and murine cDNA libraries.
Wagner et al. (1998) identified 4 AUF1 isoforms of 37 kD (p37AUF), 40 kD (p40AUF), 42 kD (p42AUF), and 45 kD (p45AUF), which result from alternative pre-mRNA splicing. The isoforms differ by the presence or absence of a 19- and/or a 49-amino acid insert.
Wagner et al. (1998) showed that the 4 AUF1 isoforms exhibit an approximately 35-fold range in ARE-binding affinities, with p37AUF having the highest affinity and p40AUF having the lowest affinity.
Cytokine and protooncogene mRNAs are rapidly degraded through AU-rich elements in the 3-prime untranslated region. Rapid decay involves AU-rich binding protein AUF1, which complexes with heat-shock proteins HSC70 (600816) and HSP70 (see 140550), translation initiation factor EIF4G (600495), and poly(A)-binding protein (PABP; 604679). AU-rich mRNA decay is associated with displacement of EIF4G from AUF1, ubiquitination of AUF1, and degradation of AUF1 by proteasomes. Induction of HSP70 by heat shock, downregulation of the ubiquitin-proteasome network, or inactivation of ubiquitinating enzyme E1 (314370), all result in HSP70 sequestration of AUF1 in the perinucleus-nucleus, and all 3 processes block decay of AU-rich mRNAs and AUF1 protein. These results link the rapid degradation of cytokine mRNAs to the ubiquitin-proteasome pathway (Laroia et al., 1999).
AU-rich elements and protein-coding determinants direct rapid removal of poly(A) tails as a necessary first step in mRNA decay. Grosset et al. (2000) determined that 5 proteins form a multiprotein complex associated with the major protein-coding-region determinant of instability (mCRD) of the FOS gene: PABP, HNRNPD, PAIP1 (605184), NSAP1, and UNR (191510). Overexpression of these proteins stabilized mCRD-containing mRNA by impeding deadenylation.
Shchors et al. (2002) showed that expression of the apparently noncoding RNA CDIR (613568) in HeLa cells inhibited interferon-gamma (147570)-induced apoptosis in a dose-dependent manner, and that this protection was associated with elevated levels of p21 (116899) and BCL2 (151430) transcripts and protein level. CDIR bound a protein complex that contained all isoforms of AUF1 and HSP27 (HSPB1; 602195). Use of recombinant proteins revealed that AUF1, but not HSP27, directly bound CDIR. Transfection of HeLa cells with another AUF1 target, the 3-prime UTR of MYC (190080), also inhibited interferon-gamma-induced cell killing, but only in a limited manner. Shchors et al. (2002) concluded that the antiapoptotic effect of CDIR is due to the sequestration of AUF1 by CDIR, resulting in elevated levels and activity of p21 and BLC2.
Dempsey et al. (1998) found that the HNRPD gene consists of 8 exons and that use of 2 of these exons is determined by alternative splicing of the HNRPD mRNA. Wagner et al. (1998) determined that the AUF1 gene consists of 10 exons.
Using monochromosomal somatic cell hybrids, Wagner et al. (1996) localized 2 AUF1 loci to chromosomes 4 and X. By fluorescence in situ hybridization (FISH) analysis using P1 clones as probes, they identified 4q21.1-q21.2 and Xq12 as the locations of the AUF1 genes. The autosomal gene, AUF1, was alternatively symbolized AUF1A and the X-linked gene, which maps to Xq12, was provisionally symbolized AUF1B. Two different P1 clones, named G1626 and P0139, were used in the FISH analysis. These phage P1 clones were obtained from a human genomic library using the same cDNA probe used in the Southern analysis of the somatic hybrid cell panels. FISH signals were observed on chromosome 4 only with G1626, and on the X chromosome only with P0139. By FISH with labeled genomic DNAs as probes, Dempsey et al. (1998) mapped the HNRPD gene to 4q21. By the same method, they mapped the mouse Hnrpd gene to the F region of chromosome 3.
Brewer (1999) stated that AUF1B, also symbolized HNRPDP, is a pseudogene of HNRPD.
Brewer, G. Personal Communication. Winston-Salem, N.C. 3/4/1999.
Brewer, G. An A+U-rich element RNA-binding factor regulates c-myc mRNA stability in vitro. Molec. Cell. Biol. 11: 2460-2466, 1991. [PubMed: 1901943] [Full Text: https://doi.org/10.1128/mcb.11.5.2460-2466.1991]
Dempsey, L. A., Li, M., DePace, A., Bray-Ward, P., Maizels, N. The human HNRPD locus maps to 4q21 and encodes a highly conserved protein. Genomics 49: 378-384, 1998. [PubMed: 9615222] [Full Text: https://doi.org/10.1006/geno.1998.5237]
Grosset, C., Chen, C.-Y. A., Xu, N., Sonenberg, N., Jacquemin-Sablon, H., Shyu, A.-B. A mechanism for translationally coupled mRNA turnover: interaction between the poly(A) tail and a c-fos RNA coding determinant via a protein complex. Cell 103: 29-40, 2000. [PubMed: 11051545] [Full Text: https://doi.org/10.1016/s0092-8674(00)00102-1]
Laroia, G., Cuesta, R., Brewer, G., Schneider, R. J. Control of mRNA decay by heat shock-ubiquitin-proteasome pathway. Science 284: 499-502, 1999. [PubMed: 10205060] [Full Text: https://doi.org/10.1126/science.284.5413.499]
Shchors, K., Yehiely, F., Kular, R. K., Kotlo, K. U., Brewer, G., Deiss, L. P. Cell death inhibiting RNA (CDIR) derived from a 3-prime-untranslated region binds AUF1 and heat shock protein 27. J. Biol. Chem. 277: 47061-47072, 2002. [PubMed: 12356764] [Full Text: https://doi.org/10.1074/jbc.M202272200]
Wagner, B. J., DeMaria, C. T., Sun, Y., Wilson, G. M., Brewer, G. Structure and genomic organization of the human AUF1 gene: alternative pre-mRNA splicing generates four protein isoforms. Genomics 48: 195-202, 1998. [PubMed: 9521873] [Full Text: https://doi.org/10.1006/geno.1997.5142]
Wagner, B. J., Long, L., Rao, P. N., Pettenati, M. J., Brewer, G. Localization and physical mapping of genes encoding the A+U-rich element RNA-binding protein AUF1 to human chromosomes 4 and X. Genomics 34: 219-222, 1996. [PubMed: 8661052] [Full Text: https://doi.org/10.1006/geno.1996.0269]
Zhang, W., Wagner, B. J., Ehrenman, K., Schaefer, A. W., DeMaria, C. T., Crater, D., DeHaven, K., Long, L., Brewer, G. Purification, characterization and cDNA cloning of an AU-rich element RNA-binding protein, AUF1. Molec. Cell. Biol. 13: 7652-7665, 1993. [PubMed: 8246982] [Full Text: https://doi.org/10.1128/mcb.13.12.7652-7665.1993]