Disease relevance of RBP2

• RBP2, the form which has lost the two N-terminal Leu is dramatically increased in serum of patients with chronic renal failure (CRF) whereas this form is very low in normal serum [1].
• Keratinocytes, in the absence of full terminal differentiation, as well as hyperplasia, such as cultured human differentiating keratinocytes, psoriatic plaques, and non-keratinized oral mucosa, contained high levels of CRABP-II [2].
• Our findings also suggest that CRABP-II may be a potential therapeutic target for neuroblastoma [3].
• Retinoblastoma-binding protein 2 (Rbp2) was originally identified as a retinoblastoma protein (RB) pocket domain-binding protein [4].
• Therefore, in this study, we re-established the pRb-modulating function of RBP2-H1 in highly metastatic A375-SM melanoma cells by re-expressing its C-term (cRBP2-H1) [5].

High impact information on RBP2

• Here we demonstrate that the JARID1 proteins RBP2, PLU1, and SMCX are histone demethylases specific for di- and trimethylated histone 3 lysine 4 (H3K4) [6].
• RBP2 Belongs to a Family of Demethylases, Specific for Tri-and Dimethylated Lysine 4 on Histone 3 [6].
• Consistent with a role for the JARID1 Drosophila homolog Lid in regulating expression of homeotic genes during development, we show that RBP2 is displaced from Hox genes during embryonic stem (ES) cell differentiation correlating with an increase of their H3K4me3 levels and expression [6].
• Our results suggest that promotion of differentiation by pRB involves neutralization of free RBP2 and transcriptional activation of RBP2 targets linked to euchromatin maintenance [7].
• In analogy with CS, preferential repair of UV-induced cyclobutane pyrimidine dimers in the transcribed strand of the active RBP2 gene is severely impaired [8].

Biological context of RBP2

• We propose that these post-translationally modified forms of RBP occur in cells and that after their release into the blood circulation RBP2 is cleared by the kidney in healthy individuals but accumulates in the serum of CRF patients [9].
• Closing in on the BPES gene on 3q23: mapping of a de Novo reciprocal translocation t(3;4)(q23;p15.2) breakpoint within a 45-kb cosmid and mapping of three candidate genes, RBP1, RBP2, and beta'-COP, distal to the breakpoint [10].
• Assignment of the cellular retinol-binding protein 2 gene (RBP2) to human chromosome band 3q23 by in situ hybridization [11].
• Cellular retinol binding protein II (CRBP II) is an abundant, 134-residue protein present in the small intestinal epithelium [12].
• According to amino acid sequence and structure analyses, the zebrafish CRBP that we have identified resembles closely mammalian CRBP II, suggesting that it is the zebrafish orthologue of this mammalian CRBP type [13].

Anatomical context of RBP2

• Mouse-human somatic cell hybrids were used to determine that both the CRBP and CRBP II genes are located on human chromosome 3 [12].
• Previous studies have shown that retinoic acid upregulates endogenous human CRBP II gene expression in differentiated Caco-2 cells [14].
• The results indicate that the retinoic acid responsiveness of the human CRBP II promoter is mediated by an indirect mechanism and that this mechanism is associated with enterocyte differentiation [14].
• Notably, in a cell line which over-expressed CRBP, endogenous CRBP II was reduced by 5-10-fold compared with the wild type and control cell lines [15].
• The mammalian small intestine contains two related cellular retinol-binding proteins, CRBP and CRBP II, which are thought to have distinct functions [15].

Associations of RBP2 with chemical compounds

• RBP2 may have an important physiological role in retinol transport and/or recycling [9].
• There is strong evidence that RBP2 is formed in vitamin A target tissues, and that after its release into blood circulation, it is cleared by the kidney in healthy people but accumulates in the serum of CRF patients [1].
• We also measured binding of FA to a retinoic acid (CRABP-I) and a retinol (CRBP-II) binding protein and we have extended to 19 different FA our characterization of the FA-ADIFAB and FA-rat intestinal FABP interactions [16].
• However, direct sequence analysis and transient transfection experiments indicate that, unlike the rat CRBP II promoter, the human CRBP II promoter is not a direct retinoid X receptor target [14].
• Retinol uptake and retinyl ester synthesis were increased up to 2-fold by coexpression of CRBP or over-expression of CRBP II [15].

Physical interactions of RBP2

• Secondly, we found that the truncation resulting in RBP2 does not alter its binding properties for retinol nor those of holo-RBP2 for TTR [17].

Regulatory relationships of RBP2

• Stably transfected cloned Caco-2 cell lines that over-express CRBP II or coexpress CRBP and CRBP II and a control cell line that contains the expression vector without an insert were established [15].

Other interactions of RBP2

• Furthermore, we demonstrate that CRABP-II is actually the CRABP previously studied in epidermal cells by a PAGE assay (Siegenthaler & Saurat (1987) Eur. J Biochem. 166, 209-214) and whose levels are dramatically increased by retinoic acid and its analogues in human epidermis [2].
• Immunohistochemical analysis with the antiserum alpha-PLU-1C confirmed the nuclear localisation of PLU-1. alpha-PLU-1C also reacted with the mouse homologue of PLU-1 (mPlu-1) but not with the closest family member, RBP2 [18].
• Retinoic acid receptor beta and apolipoprotein A1 regulatory protein-1, two nuclear receptors that bind to the CRBPII promoter, were also induced, whereas other retinoid and orphan receptors were not [19].
• We found that CRBPII levels were elevated in the residual jejunal segment of rats subjected to jejunal bypass operation, where a concomitant increase in the apoprotein B levels occurred [20].
• In the 5'-flanking region of rat CRBPII gene, two DR-1 type elements which consist of a direct repeat of the AGGTCA-like motif spaced by a single nucleotide have been identified as putative binding sites for a heterodimer of peroxisome proliferator-activated receptor (PPAR) and retinoid X-receptor (RXR) [20].

Analytical, diagnostic and therapeutic context of RBP2

• Immunoblot and Northern blot hybridization demonstrated that Caco-2 cells express CRBP II and cellular retinoic acid-binding protein I in increasing amounts as the cells become more differentiated but do not express detectable quantities of CRBP [15].
• A polymerase chain reaction (PCR) method has been validated for the quantitation of retinoic acid (RA) induction of cellular retinoic acid-binding protein II (CRABP-II) RNA from cultured human skin fibroblasts and human skin biopsies [21].
• The interaction between RBTN2 and RBP2 was confirmed using in vitro binding assays, and by co-immunoprecipitation of the two proteins [22].
• Electrophoretic mobility shift assay using the DR-1 type cis-elements of CRBP II gene showed that PPARalpha-RXRalpha heterodimer was capable of binding to these elements, and that nuclear extracts from the jejunum of rats fed the high-fat diet gave greater density of retarded bands than those of rats fed a fat-free diet [20].
• The organ culture of day 16 embryonic chick duodenum showed that the addition of 9-cis retinoic acid in the medium caused a significant increase in CRBP II mRNA levels [23].

References