This ancient member of the cold shock protein family plays a pivotal role in numerous diseases.

ALIAS

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Alternate Names: BP-8, CSDA2, CSDB, DNA-binding protein B, DBPB, Enhancer factor I subunit A antibody; EFI-A antibody MDR-NF1, MGC104858, MGC110976, MGC117250, nuclease sensitive element binding protein 1, NSEP-1, NSEP1, p50, YB-1, YB1, OTTHUMP00000008731 | Chromosome human: 1; Location: 1p34 | Annotation: Chromosome 1, NC_000001.9 (42920653..42940607) | MIM: 154030 | GeneID: 4904 (Human)

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BACKGROUND

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The Y-box binding protein 1 (YBX1, YB-1) is the prototypic member of the evolutionarily conserved cold shock protein family (PMID 12815724). Other members in humans are denoted DNA-binding protein A (DbpA, (PMID7628487)) and Contrin (DbpC, (PMID 10100484)). These multifunctional proteins bind to DNA as well as RNA via their unique, centrally located cold shock domain (see Figure below).

Domains within the protein C-terminus convey specificity of binding. By virtue of its binding capacities YB-1 may alter gene transcription in the nucleus, affect pre-mRNA splicing as well as mRNA translation processes and metabolism (PMID 9704408). Of note, the binding motif that YB-1 recognizes is not well defined and is not limited to the inverted CCAAT-box (the so-called Y-box, (PMID 3174636)), originally determined in HLA-gene promoters. Therefore prediction of its target genes is rather difficult and not feasible with conventional in silico analyses. Original studies revealed that cold shock proteins rather recognize the DNA structure than a defined nucleotide sequence and may furthermore exert modifying steps (by means of endo- as well as exonuclease activities with ensuing separation of double-stranded DNA and stabilization of single-stranded loops, (PMIDs 7876087, 9830047, 11395503).

Defined target genes are summarized in Table 1 (Arrows indicate, whether the expression of the proteins are up- respectively down-regulated by YB-1).

Table 1: Genes regulated by YB-1

Target Gene	Regulation	References
Cytokines, Chemokines and Receptors
PDGF-B		10953033
RANTES		17893273,18800033
IFN-alpha & IFN-beta		1986360
GM-CSF	/	8710501, 11116154
Thyrotropin Receptor		8838147
Signal Transduction
Smad7		16278212
PTP1B		12554649
Matrix- and Matrix-Degrading Proteins
Gelatinase A (MMP-2)	/	9278454
Collagen Type 1 (alpha1)		11395503
Collagen Type 1 (alpha2)		12917425
Antigen Presentation
HLA class II		3174636
HLA class I		7651426
Proliferation
DNA-Polymerase-alpha		15615704
c-myc		10906122
Transport Proteins, Detoxification
MDR-1		9095180
MRP1		11325824
MRP2		12963034
Grp78		8972186
Structural Proteins and others
Myosin light-chain 2v		9043061
Chicken alpha-Globin		8336706
SMaA		16093352
Viral Promoters
RSV		9576478
HTLV-1		8254772
HIV		10573156
JC Polyomavirus		11517404

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The complexity of gene regulation by YB-1 is further increased due to cell-specific interactions with co-factors and other transcription factors. As result target genes may be up- as well as down-regulated by YB-1. Known interacting partners are summarized in Table 2.

Table 2: Interaction Partners of YB-1

Interacting Protein	Relevance of interaction	References
Akt	Akt/PKB phosphorylates cold shock domain at serine 102. Akt/PKB induces translocation of YB-1 into nucleus and expression of drug-resistence genes.	15806160, 17072343
Actin	YB-1 directs mRNA binding to the actin cytoskelet and thereby affects mRNA transport and translation.	10504297
AP-2 (activator protein 2)	AP-2 and YB-1 synergistically activate transcription of the MMP-2 gene.	9830047
Casein kinase II	Within the YB-1 protein phosphorylation by casein kinase II is observed.	15494450
CTCF (multivalent zink finger protein)	Coexpression of YB-1 and CTCF results in increased repression of the c-myc oncogene promoter. YB-1 alone does not have a repressive effect on the promoter.	10906122
EGFR (epidermal growth factor receptor)	YB-1 induces the EGFR expression and promotes EGF-independent proliferation of human breast epithelial cells (HMEC).	15735691
hnRNP K (heterogeneous nuclear ribonucleoprotein K)	By interacting with hnRNP K the export of RNA and its processing is directed by YB-1.	10809782
Endonuclease III	YB-1 increases the activity of human endonuclease III, an enzyme involved in initiation of excision repair.	11287425
JC virus late regulatory Agnoprotein	The viral agno-protein directly interacts with YB-1 and represses its effect on viral promoters.	11907223
Nm23-ß (non-metastasizing protein-23)	Nm23-ß and YB-1 compete for binding to an enhancer element within the MMP-2/gelatinase A gene promoter.	11287425
Nucleolin	Nucleolin and YB-1 stabilize mRNA of interleukin-2 by binding to the 5’-untranslated region (Utr).	10817758
p53	p53 and YB-1 interact via 3 distinct domains. p53 requires YB-1 for activation of the p21 gene. YB-1, AP-2 und p53 form a trimeric complex and coordinately promote transcription of the gelatinase A gene.	10817758
Pur alpha	YB-1 and Pur alpha interact and thereby alter their binding abilities to the human JC-virus promoter, thereby synergistically stimulating transcription of the viral genome.	10573156
Pur beta	YB-1/MSY-1 and Pur alpha/Pur beta reduce gene transcription of alpha-smooth muscle actin.	10573156
p300/Smad3	YB-1 suppresses collagen gene transcription and directly interacts with p300/CBP. Thereby, p300/CBP no longer cooperates with Smad3 protein, blunting the stimulatory effect that TGF-ß signalling has on collagen synthesis.	16278212, 12917425
RelA (p65)	YB-1 directly interacts with NF-kappaB subunit p65 and increases its affinity for NF-kappaB binding sites within the viral JC late promoter. The outcome is synergistic activation of gene transcription.	8709216
SRp30c (member of Serine-Rich protein family)	Via a direct protein interaction splicing factor SRp30c shuttles YB-1 to the nuclear compartment. There, concerted actions alter pre-mRNA splicing.	12604611
T-antigen of human polyomavirus JC	The interaction of YB-1 with the viral JC-T-Antigen synergistically trans-activates the viral late promoter. Furthermore, YB-1 promotes repression of the viral early promoter via the T-antigen.	10573156
TLS (translocation liposarcoma protein)	A direct interaction with TLS recruits YB-1 to the RNA-polymerase II and thereby affects splicing.	11325824
VEGF (vascular endothelial growth factor)	VEGF binds to cold shock domain (CSD) and confers stability of mRNA	14728692
ZO-1 (Zona occludens Protein-1)	YB-1 represses the c-Erb promoter. With formation of cell adhesions and expression of ZO-1 there is recruitment of YB-1 to ZO-1 molecules and the inhibitory effect on c-Erb expression is released.	12566432
Microtubulules	YB-1 promotes microtubule formation.	18652827, 18793384

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One of the best studied YB-1 protein interactions relates to the tumor-suppressor protein p53. Hereby, transcriptional activities of p53 are markedly altered (PMIDs 16158057, 12835324, 12743601). Overall, YB-1 seems to direct cell proliferation (12695516), DNA replication (15615704), DNA repair (17686777), detoxification (18809583), cytokine (11698476, 10817758, 14662883) and matrix synthesis (PMIDs 11395503, 9278454, 11973333). Most insights have been gained into the role of YB-1 for cancerogenesis, e.g. of breast cancer (PMIDs 9095180, 15899797, 15735691, 15806160). Experimental models demonstrated that YB-1 overexpression in breast tissue induces chromosomal instability and breast cancer in all transgenic animals over a year (PMID 15899797). In breast cancer YB-1 expression levels are excellent indicators for long-term survival over all subtypes of disease (PMID 18925950). Besides breast cancer, YB-1 expression is upregulated in non-small cell lung carcinoma (PMID 14738225), ovarian adenocarcinomas (10357417, 17459055), human osteosarcomas (12533839, 9748149), colorectal carcinomas (10597187, 18214301), and malignant melanomas (17266041), amongst others.

Recent studies emphasize the role that YB-1 also plays in other, diverse diseases, given that intervention in the cellular YB-1 expression by means of small interfering RNA altered the course of diseases. The most prominent findings relate to:

• Chemotherapy sensitivity/P-glycoprotein (MDR-1) expression (9095180, 12533839)
• Atherosclerosis (17893273)
• Liver fibrosis (16012952)
• Transplant rejection / Monocyte activation (18800033)
• Allergic Asthma (11698476)

The plethora of functions is further underscored by the effects that YB-1 has on the RNA metabolism. mRNA half lifes are largely dependent on the cellular YB-1 content and YB-1 is a major part of the heterogenous ribonucleoprotein particles (hnRNP), in this context it is also denoted p50 (16721060). A prominent example of its role in the orchestration of mRNA stability is provided with IL-2 transcripts in T-lymphocytes (10817758). The functions fulfilled by YB-1 take place in the nucleus as well as in the cytoplasm. In vitro, YB-1 may be detected in both compartments by western blotting and immunofluorescence. Nuclear translocation is cell cycle-regulated, with YB1 protein accumulating in the nucleus during G1/S phase (12695516). On the other hand cells stressed by UV light, hyperthermia or diverse cytokines (like IFN-gamma, insulin-like growth factor-1) and thrombin induce nuclear shuttling of YB-1 (12917425, 10953033). In vivo the detection of YB-1 is difficult, as most antibodies do not render a positive signal with formalin-fixed tissue. Reports exist that show a nuclear staining in healthy tissue when fixation was performed with Methacarn fixation. In cancer tissue of different origin staining of cytoplasmic YB-1 is often detected with different antibodies, however the nuclear detection mostly fails in most cases where polyclonal antibodies have been utilized. The determination of the precise subcellular localization of YB-1 seems to be crucial, as nuclear expression correlates with high levels of proliferation, drug resistance, and poor tumor prognosis (18925950, 18316615, 11774277). Within the protein a crucial phosphorylation site at serine 102 has been mapped that is the substrate of Akt/PKB enzyme activity. In cancerogenesis this phosphorylation step may be of relevance and conveys nuclear shuttling (15806160, 19036157). Treatment of the MCF-7 breast cancer cell line with IGF-1 results in Akt-mediated phosphorylation of YB1 on Ser102. This promotes anchorage-independent growth ((15806160, 17875215). Some events induce limited proteolysis of the protein within the protein C-terminus by the 20S proteasome. The N-terminal fragment has distinct functions and shuttles to the nucleus. Degradation mechanisms for the N-terminal as well as C-terminal fragments have been unraveled (16797541, 16193061).

YB-1 ANTIBODIES

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Under exclusive license antibodies-online offers a unique set of antibodies that are specific for cold shock proteins:
	YB-1 N-terminal antibody (ABIN155053): directed against a unique epitope within the protein N-terminus. Applications tested include western blotting and immunohistochemistry (of Methacarn fixed tissue) with cancer tissue as well as non-cancer tissue. This antibody detects mouse, rat and human YB-1. » Go to datasheet
	YB-1 C-terminal antibody (ABIN155055): directed against an unique epitope within the protein C-terminus. Applications tested include western blotting. This antibody does not work for immunohistochemistry/immunofluorescence microscopy. This antibody detects mouse, rat and human YB-1. » Go to datasheet
	Monoclonal anti-YB-1 antibody (ABIN173291): detects human YB-1 in cancer tissue by immunohistochemistry, best as biotinylated antibody. » Go to datasheet
	DbpA antibody (ABIN155054): directed against a unique epitope within the protein N-terminus. This antibody is suited for western blotting as well as immunohistochemistry/immunofluorescence microscopy. It detects human DbpA protein. » Go to datasheet

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