YBX1 (Y box binding protein 1)

	Genomic organization of YBX1. Box = exon (blue = 5'UTR, yellow = CDS, light red = 3'UTR). Line = intron.
Description	The human YBX1 gene consists of 8 exons and 7 introns spanning a 19.2-kb genomic region. Intron number 1 is phase 1 (between 1st and 2nd base of codon). Introns number 2 and 6 are phase 2 (between 2nd and 3rd base of codon). Introns number 3, 4, 5 are phase 0 (between codons). According to the SNP source (dbSNP NCBI), non-synonymous polymorphism has been reported for the codons 30 (rs11558135), 237 (rs3887881), 251 (rs55676223), and 261 (rs3887879). The YBX1 promoter region contains no typical TATA or CCAAT box, but has multiple E-boxes located between -1855 and -422 nucleotides (relative to the start of exon 1) and several GT and GC boxes. The gene also contains a large and highly conserved CpG island at the immediate 5' promoter region which extends to the first exon encoding 5' UTR of YBX1 mRNA. The region between nucleotides -119 to +127 was shown to be essential for transcriptional activity in the reporter assays (Makino et al., 1996). YBX1 is constitutively expressed in multiple human tissues and its expression can be further induced by the E-box-binding transcription factors such as c-myc (Uramoto et al., 2002), Twist (Shiota et al., 2008) and Math2 (Ohashi et al., 2009).
Transcription	The main processed mRNA is 1514 bp. It encompasses exons 1-8. The 70-amino acid cold-shock domain (CSD) is encoded separately by exons 2-5. Four additional splice variants in human were predicted (Ensembl), two of which (YBX1-004 and YBX1-201) preserve exons 2 and 3 coding for core elements of the CSD, the RNP1 and RNP2 motifs, respectively. An alternative transcript for ctYB-1, the YBX1 homologous gene in C. tentans, has been reported (Nashchekin et al., 2007).
Pseudogene	Description Symbol NCBI gene ID Position Introns/exons ORF Identity with YBX1 Gaps nuclease sensitive element binding protein 1 pseudogene bA327L3.4 158373 9p13.1 Intronless Stops after E88 1477/1515 (97%) 2/1515 (0%) Y box binding protein 1 pseudogene 1 YBX1P1 50631 4q23.3 Intronless 1496 bp - 1488/1531 (97%) 20/1511 (1%) Y box binding protein 1 pseudogene 2 YBX1P2 646531 7q22.3 2 exons, 1 intron, 1553 bp Stops after E88 1431/1529 (93%) 43/1529 (2%) Y box binding protein 1 pseudogene LOC100131012 100131012 7q36.1 Intronless, 820 bp - 287/353 (81%) 26/353 (7%)

	Structural and functional organization of YB-1. YB-1 is composed by three domains: N-terminal Ala/Pro rich (AP) domain, cold shock domain (CSD) and the C-terminal domain (CTD) containing clusters of positively and negatively charged amino acids. Indicated are some known molecular partners of YB-1 and sites of their interactions (from Sorokin et al., 2005). The arrow indicates proteasomal cleavage sites.
Description	The YBX1 gene encodes the Y-box protein 1 (YB-1) which consists of 324 amino acid residues and has the isoelectric point 10.3. Theoretical MW is 35924, however YB-1 is known to migrate as a ~45-50 kDa protein in SDS-polyacrylamide gels due to its anomalous electrophoretic mobility. YB-1 belongs to the family of multifunctional DNA/RNA binding proteins that are highly conserved throughout evolution and found in eukaryotes, prokaryotes and archaea. The most conserved region in YB-1 is the 80 amino acid CSD which exhibits >40% identity and >60% similarity to the major E. coli cold shock protein CspA (Matsumoto and Wolffe, 1998; Sommerville, 1999). The CSD possesses RNP1 and RNP2-like consensus motifs and is represented by a five-stranded beta-barrel structure which creates a surface rich in aromatic and basic amino acids that may act as a large nucleic acid-binding site (Wolffe et al., 1992; Wolffe, 1994). The CSD has a preference for binding single-stranded pyrimidine-rich sequences. The N-terminal AP domain of YB-1 is similar to that found in several other transcription factors and may thus be important for its transcriptional activity. This region is also essential for interaction with p53 and modulation of p53-mediated transcription (Okamoto et al., 2000), and for association with actin microfilaments and mRNA compartmentalization (Ruzanov et al., 1999). The C-terminal region of YB-1 is responsible for sequence-nonspecific binding to DNA and RNA and mediation of protein-protein interactions (Wolffe, 1994; Sommerville and Ladomery, 1996). An inverted CCAAT-box found in HLA class II gene promoters, a so-called Y-box, was originally determined as the YB-1 binding motif (Didier et al., 1988). Later studies have concluded that YB-1 rather recognizes the DNA structure than a defined nucleotide sequence, making prediction of its target genes not feasible with conventional in silico analyses (Swamynathan et al., 1998). YB-1 is also capable of unwinding DNA and RNA duplexes, especially those containing mismatches, thereby promoting strand exchange and formation of perfectly matched duplex structures (Skabkin et al., 2001; Gaudreault et al., 2004).
Expression	According to Human Protein Atlas, YB-1 is variably expressed in most normal human tissues. Its expression is elevated in multiple cancer types (Kohno et al., 2003).
Localisation	Mostly cytosolic. Shuttles between cytoplasm and nucleus. Localized in cytoplasmic stress granules and processing bodies containing untranslated mRNAs (Kedersha and Anderson, 2007). Nuclear translocation is induced in response to various stresses, including adenoviral infection (Holm et al., 2002), hyperthermia (Stein et al., 2001), DNA damage (Kohno et al., 2003) and activation of PI3K-Akt signaling (Sutherland et al., 2005).
Function	The diverse biological functions of YB-1 appear to arise from its broad nucleic acid binding properties. YB-1 has been implicated in pre-mRNA splicing, transcriptional regulation, mRNA translation and stability as well as in chromatin remodelling, DNA repair and environmental stress responses (Kohno et al., 2003; Matsumoto and Bay, 2005). Splicing. YB-1 regulates splice site selection via direct binding to splicing recognition motifs in pre-mRNA, including A/C-rich exon enhancers (Stickeler et al., 2001) or via interaction with splicing factors from the SR family (Li et al., 2003; Raffetseder et al., 2003). Transcription. YB-1 is capable of binding to promoters of many genes, many of which lack the Y-box, and either activates or represses transcription. Among the genes activated by YB-1 are thymidine kinase, proliferating cell nuclear antigen (PCNA), cyclin A and cyclin B1, DNA topoisomerase II alpha, gelatinase A, matrix metalloproteinase 2, multidrug resistance 1 (MDR1), EGFR and protein tyrosine phosphatase 1B. Genes that are transcriptionally repressed by YB-1 include MHC class II, collagen alpha1, granulocyte-macrophage colony-stimulating factor (GM-CSF), etc (reviewed in Ladomery and Sommerville, 1995; Kohno et al., 2003; Kuwano et al., 2003). Overall, YB-1 is considered as an important regulator of growth- and stress-associated genes. mRNA translation and stability. YB-1 (p50) is known as a major structural component of messenger ribonucleoprotein particles (mRNPs) which exerts positive or negative effects on translation, depending on the amount bound to mRNA (Evdokimova and Ovchinnikov, 1999). YB-1 regulates translational activity of many growth- and differentiation-associated mRNAs, including Snail1, and selectively protects capped mRNAs against degradation (Evdokimova et al., 2001; Evdokimova et al., 2006; Evdokimova et al., 2009). YB-1 appears to play a role in stabilization of short-lived mRNAs, including IL-2 (Chen et al., 2000), GM-CSF (Capowski et al., 2001) and VEGF (Coles et al., 2004). DNA repair and stress response. YB-1 is involved in base excision and mismatch repair pathways via interaction with multiple DNA repair proteins including glycosylase NEIL2, DNA polymerase beta and delta, DNA ligase III, APE1, MSH2, Ku80, WRN, endonuclease III, etc (Marenstein et al., 2001; Gaudreault et al., 2004; Das et al., 2007). YB-1 also directly binds and promotes separation of DNA strands that contain mismatches or are modified by cisplatin (Ise et al., 1999; Skabkin et al., 2001; Gaudreault et al., 2004). Various stresses, including DNA damage, adenovirus infection and hyperthermia, induce nuclear translocation of YB-1 (Ohga et al., 1996; Kohno et al., 2003) and its proteasomal cleavage (Sorokin et al., 2005). Accumulation of the full-length and/or truncated YB-1 proteins in the nucleus is associated with increased survival and multidrug resistance (Kohno et al., 2003; Sorokin et al., 2005). YB-1 knock-out in mice is lethal (Lu et al., 2005; Lu et al., 2006). Fibroblasts derived from YB-1(-/-) embryos exhibit a reduced ability to respond to oxidative, genotoxic and oncogene-induced stresses, further implicating YB-1 in stress responses and embryonic development. Tumorigenesis. YB-1 is frequently overexpressed in multiple human cancers (reviewed in Kohno et al., 2003; Kuwano et al., 2003). In many cases, YB-1 levels are elevated in the nucleus, positively correlating with multiple drug resistance and poor patient outcome (Bargou et al., 1997; Janz et al., 2002). Ectopic expression of YB-1 in breast cancer cells and mouse models stimulated tumor growth (Bergmann et al., 2005; Sutherland et al., 2005). Yet, the role of YB-1 in tumorigenesis is controversial. YB-1 overexpression blocked oncogenic transformation caused by PI3K or Akt (Bader et al., 2003). These apparently contradictory results were proposed to be due to differential localization of YB-1; its interference with oncogenic transformation is associated with cytosolic localization and a consequent function in translational control (Bader and Vogt, 2004; Bader and Vogt, 2005).
Homology	YB-1 is highly homologous to human DbpA (12p13; expressed predominantly in heart and muscle) and DbpC/contrin (17p11; expressed exclusively in germ cells). They share greater than 90% identity within the CSD and a high degree of similarity in the N- and C-terminal domains, including C-terminal clusters of basic and acidic amino acids. Mouse orthologues are YB-1 (encoded by Ybx1; 99% overall aminoacid identity with human YB-1), MSY2 (Ybx2; ~93% identity with contrin) and MSY4 (~86% identity with DbpA).

Search in all EBI   NCBI

For comments and suggestions or contributions, please contact us