Disease relevance of TRNAP2

• While immunization of mice with DCs pulsed with an antigenic peptide derived from the human TRP2 protein generated partial protective immunity against B16 tumor, immunization with DCs loaded with a TAT-TRP2 peptide resulted in complete protective immunity, as well as significant inhibition of lung metastases in a 3-day tumor model [1].
• These results suggest that TRP2 may be useful for the development of murine tumor immunotherapy models and for the treatment of melanoma patients who are diverse in HLA expression [2].
• We previously showed that genetic immunization of C57BL/6 mice with recombinant adenovirus encoding human TRP2 (Ad-hTRP2) was able to circumvent tolerance and induce cellular and humoral immune responses to murine TRP2 associated with protection against metastatic growth of B16 melanoma [3].
• To address these issues, we compared the vaccination efficacy of three well established strategies (i.e., naked DNA; peptide-pulsed dendritic cells (DC), or a mixture of peptide and the Escherichia coli toxin LTR72) using the xenogeneic OVA or the naturally expressed tyrosinase-related protein 2 (TRP-2) tumor Ag in the B16 melanoma model [4].
• Melanoma patients who developed hypopigmentation and had improved survival after polyvalent melanoma cell vaccine had significantly augmented anti-TRP-2 antibody responses compared with patients with poor prognosis [5].

High impact information on TRNAP2

• Glycerol gradient sedimentation and UV cross-linking experiments indicate that TRP-1 is a large heteromeric complex containing a 185-kD RNA-binding protein, whereas TRP-2 activity derives from a family of 110- to 70-kD proteins [6].
• A tryptophan (Trp) allele (Trp2) was recently discovered in the COL9A2 gene that is associated with dominantly inherited LDD but is only present in about 4% of Finnish patients with LDD [7].
• In this paper we identify a normal tissue differentiation antigen, tyrosinase-related protein 2 (TRP-2), expressed by the murine B16 melanoma which was found by screening a cDNA library from B16 with tumor-reactive cytotoxic T lymphocytes (CTL) [8].
• Like other melamona differentiation antigens, TRP-2 was only expressed in melanoma, melanocytes, and retina, but not in other human tissues tested [9].
• Here we report that TRP-2 was identified as a second tumor antigen recognized by a HLA-A31-restricted CTL clone derived from the TIL586 cell line [9].

Biological context of TRNAP2

• Further, a classical cAMP response element-like motif participates in the cAMP responsiveness of the TRP2 promoter, demonstrating that the TRP2 gene is subjected to different regulatory processes, which could account for its different expression patterns during embryonic development or under specific physiological and pathological conditions [10].
• Importantly, processing of a second TRP2-derived epitope, TRP2(288-296), was diminished in IFN-gamma-treated cells, even in the absence of immunoproteasome up-regulation [11].
• Induction of antibody (Ab) response and T-cell immunity toward TRP2 with DNA plasmid vaccines has not been efficient to date [12].
• Two vaccinations (prime/boost) were essential for induction of strong anti-TRP2 cell-mediated immunity [12].
• In contrast to those of hominoids and OW monkeys, the howler TRP2 sequences have none of the characteristics of pseudogenes [13].

Anatomical context of TRNAP2

• The TRP2 allele of COL9A2 is an age-dependent risk factor for the development and severity of intervertebral disc degeneration [14].
• DCs loaded with a peptide derived from tyrosinase-related protein 2 (TRP2) covalently linked to a CPP1 sequence retained full capacity to stimulate T cells for at least 24 h, completely protected immunized mice from subsequent tumor challenge, and significantly inhibited lung metastases in a 3-day tumor model [15].
• Tyrosinase-related protein 2 (TRP2) is a melanosomal enzyme expressed in most mammalian melanocytes and melanomas [2].
• One peptide, TRP2(180-188) (SVYDFFVWL), induced CTLs from three of four patients that specifically recognized peptide-pulsed T2 cells, COS-7 cells expressing HLA-A*0201 and TRP2, and HLA-A2+ TRP2+ melanomas [2].
• Fifty-one peptides were selected from TRP2 based on a permissive HLA-A*0201 binding motif, and the 21 peptides with the highest experimentally determined binding affinities were used to stimulate peripheral blood lymphocytes from HLA-A*0201+ melanoma patients in vitro [2].

Associations of TRNAP2 with chemical compounds

• Different cis-acting elements are involved in the regulation of TRP1 and TRP2 promoter activities by cyclic AMP: pivotal role of M boxes (GTCATGTGCT) and of microphthalmia [10].
• In contrast, TRP-2 transcripts were reduced by approximately 40% in number after betamethasone-17-valerate treatment, whereas the two sex steroids, diethylstilbestrol and estradiol, caused an upregulation of about 20-fold of the initial TRP-2 transcript level [16].
• These results are different from the mechanisms by which other melanogenic agents, such as cholera toxin and isobutyl methylxanthine, stimulated melanogenesis, whereby the amounts of tyrosinase, TRP-1 and TRP-2 were increased [17].
• To determine the precise chromosomal localization of tyrosine related protein-1 and -2 (TRP-1 and TRP-2) genes by fluorescence in situ hybridization, we used DNAs isolated from human bacterial artificial chromosome clones [18].
• In melanocytes, the most effective autoprotecting mechanisms are the existence of malanosomes as a confined site for melano-synthesis and the action of tyrosinase-related protein 2 (TRP2) to drive L-dopachrome to 5,6-dihydroxyindole-2-carboxylic acid minimizing the formation of 5,6-dihydroxyindole [19].

Regulatory relationships of TRNAP2

• This study demonstrated that CCL21 was an effective adjuvant to enhance TRP2-specific immunity induced by a plasmid DNA cancer vaccine [12].

Other interactions of TRNAP2

• Enhancement of Immunity by a DNA Melanoma Vaccine against TRP2 with CCL21 as an Adjuvant [12].
• Trp2 was found only in affected individuals (4%), whereas Trp3 was present in both affected (24%) and unaffected (9%) individuals [14].
• Here, we analyzed the generation of an HLA-A*0201-presented epitope derived from the melanoma antigen tyrosinase-related protein 2 (TRP2) [11].

Analytical, diagnostic and therapeutic context of TRNAP2

• Additionally, quantitative real-time PCR (qRT-PCR) analysis disclosed that expression of mRNAs for tyrosinase, TRP1 and TRP2 was suppressed by butin (7) [20].
• The lack of TRP-2 was further confirmed by western blot analyses [21].
• Sequence analysis of two clones found repressed in melanoma cell lines in earlier studies showed 9F2 to be identical with the TRP-1 gene and 6F5 with TRP-2 containing a long untranslated 3' end [22].
• Overall, it seemed that RT-PCR for tyrosinase has limited value for identifying melanoma cells in the peripheral blood of melanoma patients; TRP-1, TRP-2, and other, additional markers may be required [22].
• In addition, mRNA of TRP-1 and TRP-2 were also increased after treatment with scoparone [23].

References