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Biomedical subjects

K Ozato

Publications and source records attributed to K Ozato.

At least 127 records · Page 7Linked to original sources
PubMed1993

The genomic structure of the murine ICSBP gene reveals the presence of the gamma interferon-responsive element, to which an ISGF3 alpha subunit (or similar) molecule binds.

ICSBP, a member of the interferon regulatory factor family, is expressed predominantly in lymphoid tissues and is induced by gamma interferon (IFN-gamma). We have studied the genomic organization of the murine ICSBP gene and its 5' upstream region. The murine ICSBP gene (Icsbp) is present as a single copy on chromosome 8 and consists of nine exons. Transcription initiates at two juxtaposed sites downstream from the TATA and CAAT boxes and produces two species of ICSBP mRNA (3.0 and 1.7 kb), presumably by differential usage of poly(A)+ signals. A sequence from -175 to -155 was identified to be an IFN response region that conferred IFN-gamma induction upon a heterologous promoter in lymphoid cell line EL4. This region includes a motif, TTCNNGGAA, designated the palindromic IFN response element (pIRE), to which an IFN-gamma-inducible, cycloheximide-sensitive factor(s) binds. A similar palindromic motif was found in the upstream region of the murine IRF-1 gene, the IFN-gamma activation site of the guanylate-binding protein gene and the IFN-gamma-responsive region of the Fc receptor type I gene, all of which competed with the pIRE for factor binding in gel mobility shift assays. We show that the pIRE binding factor reacts with the antibody against the 91-kDa subunit of ISGF3 alpha recently shown to bind to the IFN-gamma activation site. These results suggest that this factor is related to the IFN-gamma activation factor and contains the 91-kDa subunit of ISGF3 alpha. Taken together, pIRE represents an IRE that is distinct from the classical IFN-stimulated response element and that is capable of conferring IFN-gamma induction through the binding of the 91-kDa ISGF3 alpha subunit (or an antigenically similar molecule).

Animals↗
PubMed1993

Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene.

The vitamin D receptor (VDR) binds the vitamin D-responsive element (VDRE) as a heterodimer with an unidentified receptor auxiliary factor (RAF) present in mammalian cell nuclear extracts. VDR also interacts with the retinoid X receptors (RXRs), implying that RAF may be related to the RXRs. Here we demonstrate that highly purified HeLa cell RAF contained RXR beta immunoreactivity and that both activities copurified and precisely coeluted in high-resolution hydroxylapatite chromatography. Furthermore, an RXR beta-specific antibody disrupted VDR-RAF-VDRE complexes in mobility shift assays. These data strongly indicate that HeLa RAF is highly related to or is identical to RXR beta. Consequently, the effect of the 9-cis retinoic acid ligand for RXRs was examined in 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]-activated gene expression systems. Increasing concentrations of 9-cis retinoic acid (1 nM to 1 microM) markedly reduced 1,25(OH)2D3-dependent accumulation of osteocalcin mRNA in osteoblast-like ROS 17/2.8 cells. All-trans retinoic acid also interfered with vitamin D responsiveness, but it was consistently less potent than the 9-cis isomer. Transient transfection studies revealed that attenuation by 9-cis retinoic acid was at the transcriptional level and was mediated through interactions at the osteocalcin VDRE. Furthermore, overexpression of both RXR beta and RXR alpha augmented 1,25(OH)2D3 responsiveness in transient expression studies. Direct analysis of VDRE binding in mobility shift assays demonstrated that heteromeric interactions between VDR and RXR were enhanced by 1,25(OH)2D3 and were not affected appreciably by 9-cis retinoic acid, except that inhibition was observed at high retinoid concentrations. These data suggest a regulatory mechanism for osteocalcin gene expression that involves 1,25(OH)2D3-induced heterodimerization of VDR and unliganded RXR. 9-cis retinoic acid may attenuate 1,25(OH)2D3 responsiveness by diverting RXRs away from VDR-mediated transcription and towards other RXR-dependent transcriptional pathways.

Animals↗
PubMed1992

Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes.

The promoter regions of many interferon-inducible genes share a short DNA sequence motif, termed the interferon consensus sequence (ICS) to which several regulatory proteins bind. A murine cDNA which encodes an ICS binding protein has been reported (M-ICSBP). The cloning of the human homologue of ICSBP (H-ICSBP) is described. H-ICSBP shares high sequence homology with its murine cognate. The derived sequence of H-ICSBP reveals restricted homology within the first 120 amino acids to three other interferon regulatory factors, IRF-1, IRF-2, and ISGF3 gamma. Truncated ICSBP lacking the first 33 amino-terminal amino acids fails to bind to the ICS, indicating that at least part of the DNA binding domain is located within the well conserved amino terminus. H-ICSBP is expressed exclusively in cell lines of hematopoietic origin. The results of transient transfection assays carried out either in hematopoietic or nonhematopoietic cells suggest that ICSBP acts as a negative regulatory factor on ICS-containing promoters. Furthermore, either interferon-gamma (IFN-gamma) or IFN-beta can alleviate the repression mediated by ICSBP. Therefore, ICSBP may be involved in maintaining submaximal transcriptional activity of IFN-inducible genes in hematopoietic cells. IFN treatment would then alleviate repression allowing maximal transcriptional activity of these genes.

Amino Acid Sequence↗
PubMed1992

Heterodimerization of thyroid hormone (TH) receptor with H-2RIIBP (RXR beta) enhances DNA binding and TH-dependent transcriptional activation.

Steroid/TH receptors mediate transcriptional induction of promoters containing hormone response elements (HREs) through an unclear mechanism that involves receptor binding to both hormone and a HRE. Here we demonstrate that both HRE binding and the transcriptional inducing activities of one member of this family, TH receptor, were markedly enhanced by heterodimerization with H-2RIIBP, a non-TH-binding member of the steroid hormone receptor superfamily. H-2RIIBP, the mouse homologue of human retinoic acid-related receptor, was shown to form stable heterodimers with the TH receptor either in solution or when bound to a TH response element. The results presented indicate that it might be necessary for the TH receptor or other members of this superfamily to have specific partners for heterodimer formation to elicit maximal hormone-specific gene regulation from particular HREs.

Animals↗
PubMed1992

Two upstream elements activate transcription of a major histocompatibility complex class I gene in vitro.

Expression of major histocompatibility complex (MHC) class I genes exhibits unique tissue and developmental specificity. In an effort to study molecular mechanisms of MHC class I gene regulation, an in vitro transcription system has been established. In B cell nuclear extracts a template DNA containing the mouse H-2Ld promoter sequence accurately directed RNA polymerase II-dependent transcription of a G-free cassette. A conserved class I regulatory complex previously shown to moderately enhance promoter activity in vivo enhanced transcription in vitro by 2-3 fold. Much of this enhancement was accounted for by a 40 bp fragment within the complex, which was capable of activating a basal H-2Ld promoter in either orientation. Farther downstream, another element called site B was identified, which independently activated MHC class I transcription in vitro by 2-4 fold. Site B bound a specific nuclear factor(s) through an NF-1 binding site but not through a neighboring CCAAT site. The functional significance of site B in vivo was demonstrated in transfection experiments in which site B enhanced MHC class I promoter activity to a degree comparable to that seen in vitro. With the identification of the two upstream activators, MHC class I genes may serve as a model to study roles of sequence-specific DNA-binding proteins in transcription in vitro.

Animals↗
PubMed1992

Retinoic acid-dependent transactivation of major histocompatibility complex class I promoters by the nuclear hormone receptor H-2RIIBP in undifferentiated embryonal carcinoma cells.

H-2RIIBP is a member of the nuclear hormone receptor superfamily that binds to the region II enhancer of major histocompatibility complex (MHC) class I genes. The binding occurs through the GG(T/A)CA motif present also in many other genes. The role of H-2RIIBP in developmental regulation of MHC class I genes has been studied in undifferentiated N-Tera2 embryonal carcinoma cells by transient cotransfection of an expressible H-2RIIBP plasmid and a chloramphenicol acetyltransferase reporter gene linked to the MHC class I promoter. Transfection of the expression plasmid led to production of H-2RIIBP transcripts and enhanced MHC class I promoter activity in cells that were treated with retinoic acid but not yet differentiated. Retinoic acid concentrations required for transactivation overlapped with those capable of inducing morphological differentiation and expression of endogenous MHC class I genes in these cells. This enhancement was mediated by region II, as a heterologous thymidine kinase promoter driven by region II also served as a target for H-2RIIBP transactivation. Deletion of the bulk of the DNA-binding domain or the ligand-binding domain of H-2RIIBP, but not of the N-terminal domain, abolished transactivation, indicating that the former two domains are critical for the enhancement. Moreover, H-2RIIBP transactivation exhibited a strict cell-type restriction. As observed in other cell lines, N-Tera2 cells that had undergone differentiation failed to elicit transactivation, suggesting that H-2RIIBP acts in concert with a cofactor expressed in undifferentiated N-Tera2 cells that requires retinoic acid for its function. These results suggest that H-2RIIBP can function as a developmentally specific transcription factor for MHC class I genes.

Base Sequence↗
PubMed1992

Modulation of interferon consensus sequence binding protein mRNA in murine peritoneal macrophages. Induction by IFN-gamma and down-regulation by IFN-alpha, dexamethasone, and protein kinase inhibitors.

IFN play a central role in the activation of macrophages by inducing the expression of several proteins which, in turn, result in increased functional capabilities. Homologous interferon responsive sequences have been found in many IFN-inducible genes, and the gene for a protein that binds these sequences (interferon consensus sequence binding protein, ICSBP) has recently been cloned. In this study, the regulation of ICSBP mRNA induction by IFN-gamma was characterized in murine thioglycolate-elicited peritoneal macrophages. Northern blot analysis revealed two ICSBP mRNA species from these cells. Steady-state levels of both of these species were elevated by IFN-gamma at doses consistent with many IFN-gamma-induced macrophage functional responses. ICSBP mRNA levels increased within 1 h of IFN-gamma treatment, peaked between 4 and 6 h, and subsequently declined to approach baseline levels by approximately 24 h. IFN-alpha, at a concentration shown previously to modulate macrophage surface markers and functions, had no effect on ICSBP message levels alone, but antagonized the IFN-gamma-induction of ICSBP mRNA. IFN-gamma-induction of ICSBP mRNA is resistant to cycloheximide but sensitive to protein kinase inhibitors (H7, H8, HA-1004, staurosporine) at doses that suggest that protein kinase C is a likely target. ICSBP mRNA induction is also inhibited by dexamethasone, a synthetic glucocorticoid, well known as an anti-inflammatory drug capable of influencing gene expression in macrophages. The characterization of ICSBP mRNA regulation should help identify functions for this putative IFN trans-acting factor in macrophage activation.

Animals↗
PubMed1992

H-2RIIBP (RXR beta) heterodimerization provides a mechanism for combinatorial diversity in the regulation of retinoic acid and thyroid hormone responsive genes.

H-2RIIBP (RXR beta) is a member of the nuclear hormone receptor superfamily that activates transcription of MHC class I genes in response to retinoic acid (RA). Using chemical cross-linking, co-immunoprecipitation, gel mobility shift and streptavidin-biotin DNA precipitation assays, we show that H-2RIIBP formed heterodimers with thyroid hormone (T3) and RA receptors (T3R alpha and RAR alpha). H-2RIIBP heterodimer formation required a conserved sub-domain of its C-terminal region, occurred independently of target DNA and was much more efficient than either T3R alpha/RAR alpha heterodimer or H-2RIIBP homodimer formation. Heterodimers displayed enhanced binding to target DNA elements and contacted DNA in a manner distinct from that of homodimers. A functional role for heterodimers in vivo was demonstrated by synergistic enhancement of MHC class I transcription following co-transfection of H-2RIIBP with T3R alpha or RAR alpha. We provide biochemical evidence that H-2RIIBP formed heterodimers with several naturally occurring nuclear proteins. The results suggest that H-2RIIBP, by virtue of its ability to heterodimerize, enhances combinatorial diversity and versatility in gene regulation mediated by nuclear hormone receptors.

Amino Acid Sequence↗
PubMed1992

Activation of immunoglobulin control elements in transgenic mice.

To assess the role interleukins and mitogens play in regulating immunoglobulin (Ig) gene expression via the Ig enhancer and promoter, transgenic mice carrying two different Ig gene regulatory regions were generated. One, EmukCAT, contains the Ig heavy chain enhancer (Emu) and the kappa light chain promoter driving the chloramphenicol acetyltransferase (CAT) gene. In the other, delta EmukCAT, CAT is under the control of the kappa promoter alone. Emu and kappa relative activity were assessed by CAT assay. In EmukCAT mice, low CAT expression was consistently found in spleen, bone marrow, mesenteric lymph node, and thymus but not in brain, lung, or kidney. In delta EmukCAT mice, CAT expression was detectable just above background in lymphoid tissues, suggesting a basic level of tissue specificity in the absence of the enhancer. Whole spleen cell cultures prepared from the mice were treated with lymphokines and mitogens. Lipopolysaccharide (LPS), concanavilin A (Con A), interleukin 6 (IL-6), and interferon-gamma (IFN-gamma) increased CAT expression to varying extents in cells derived from EmukCAT mice but not in spleen cells prepared from delta EmukCAT mice. Thus, the presence of Emu, in addition to the kappa promoter, is essential for the stimulation of CAT expression mediated by these factors. B cells from EmukCAT mice were separated by density into populations of small and large cells. In untreated small B cells, no CAT expression was detected and only addition of LPS resulted in an increase in CAT expression. In large B cells, CAT was expressed at a low level without addition of exogenous factors. Incubation with LPS, IL-6, Con A and IFN-gamma caused CAT expression to increase several-fold. This transgenic system provides a means to identify exogenous factors that activate Ig enhancers and promoters.

Animals↗
PubMed1992

Interferon induction of chicken MHC class I gene expression: phylogenetic conservation of the interferon-responsive element.

The 5' upstream region of a chicken MHC class I gene BF-IV contains sequence motifs similar to the interferon consensus sequences (ICS) contained in promoters of many mammalian interferon-regulated genes. To study a possible functional role of this putative chicken ICS, an oligonucleotide spanning the upstream sequences of the BF-IV gene (-174/-194) was cloned singly or in multiple copies before the herpes TK promoter controlling the chloramphenicol acetyl transferase (CAT) gene (pBLCAT2). Transient expression studies performed with primary chicken fibroblasts (CEF) showed that the chicken ICS represses constitutive promoter activity. The chicken ICS, however, enhanced CAT activity up to 20-fold following treatment with chicken interferon (IFN). Deletion analysis of the BF-IV promoter also confirms that the upstream DNA sequences (-174/-194) contain a functional ICS recognized by chicken interferon. The murine ICS of the H2-Ld gene was also activated by chicken interferon when introduced into CEF. IFN activation of chicken ICS containing reporters was also observed in transformed chicken fibroblast lines. We show that the chicken ICS binds two specific nuclear factors present in chicken fibroblasts which are induced by interferon. These factors were also capable of recognizing the mouse ICS, suggesting the conservation of a relevant DNA-binding protein. Taken together, these data indicate that the chicken ICS motif contained in a sequence from -174 to -194 of the BF-IV gene acts as a strong interferon-response element, which has been functionally conserved during about 270 million years of separate evolution of mammals and birds.

Animals↗
PubMed1992

Expression of major histocompatibility complex (MHC) class I genes in astrocytes correlates with the presence of nuclear factors that bind to constitutive and inducible enhancers.

The molecular basis of constitutive and inducible major histocompatibility complex (MHC) class I gene expression was studied in murine astrocytes in primary culture. Astrocytes constitutively expressed MHC class I molecules and treatment of these cells with interferon-gamma (IFN-gamma) further induced expression. The conserved region containing the upstream MHC class I regulatory element (MHC-CRE) and juxtaposed interferon consensus sequence (ICS) enhanced constitutive MHC class I promoter activity. As seen with cell surface expression of MHC molecules, treatment of astrocytes with IFN-gamma increased MHC class I promoter activity. Inducible expression required the presence of the MHC-CRE/ICS enhancer region. Nuclear factors that bind to the MHC-CRE and ICS were constitutively expressed in cultured astrocytes and IFN-gamma treatment further induced binding activity both to the MHC-CRE and ICS and correlated with induction of MHC class I gene expression. This study identifies the MHC-CRE and ICS as the major cis elements in controlling MHC class I promoter activity and suggests that the expression of nuclear factor binding activities to these enhancer elements is a basic transactivating mechanism for the expression of MHC class I genes in astrocytes.

Animals↗
PubMed1992

Mapping of the mouse Rxr loci encoding nuclear retinoid X receptors RXR alpha, RXR beta, and RXR gamma.

Recently, a novel subgroup of nuclear hormone receptors called RXRs implicated for retinoid-mediated gene regulation have been identified. RXRs appear to interact with many other nuclear hormone receptors and modulate their functions. We have mapped genetic loci Rxra, Rxrb, and Rxrg encoding three RXR subtypes, RXR alpha, RXR beta, and RXR gamma, respectively, using interspecific backcross mice. None of the Rxr loci cosegregated with each other or with the retinoic acid receptor loci (Rar) mapped previously. Rxra mapped to Chr 2 near the centromere, Rxrb mapped to the H-2 region of Chr 17, and Rxrg was tightly linked to the Pbx gene on distal Chr 1. These results underscore that RXR genes are dispersed in the genome.

Animals↗
PubMed1992

Cloning of a negative transcription factor that binds to the upstream conserved region of Moloney murine leukemia virus.

The long terminal repeat of Moloney murine leukemia virus (MuLV) contains the upstream conserved region (UCR). The UCR core sequence, CGCCATTTT, binds a ubiquitous nuclear factor and mediates negative regulation of MuLV promoter activity. We have isolated murine cDNA clones encoding a protein, referred to as UCRBP, that binds specifically to the UCR core sequence. Gel mobility shift assays demonstrate that the UCRBP fusion protein expressed in bacteria binds the UCR core with specificity identical to that of the UCR-binding factor in the nucleus of murine and human cells. Analysis of full-length UCRBP cDNA reveals that it has a putative zinc finger domain composed of four C2H2 zinc fingers of the GLI subgroup and an N-terminal region containing alternating charges, including a stretch of 12 histidine residues. The 2.4-kb UCRBP message is expressed in all cell lines examined (teratocarcinoma, B- and T-cell, macrophage, fibroblast, and myocyte), consistent with the ubiquitous expression of the UCR-binding factor. Transient transfection of an expressible UCRBP cDNA into fibroblasts results in down-regulation of MuLV promoter activity, in agreement with previous functional analysis of the UCR. Recently three groups have independently isolated human and mouse UCRBP. These studies show that UCRBP binds to various target motifs that are distinct from the UCR motif: the adeno-associated virus P5 promoter and elements in the immunoglobulin light- and heavy-chain genes, as well as elements in ribosomal protein genes. These results indicate that UCRBP has unusually diverse DNA-binding specificity and as such is likely to regulate expression of many different genes.

Amino Acid Sequence↗
PubMed1992

Occupancy of upstream regulatory sites in vivo coincides with major histocompatibility complex class I gene expression in mouse tissues.

The major histocompatibility complex (MHC) class I HLA-B7 transgene carrying a 660-bp upstream sequence is expressed in the mouse with tissue specificity that parallels that of the expression of endogenous mouse MHC class I (H-2) genes. We have performed in vivo genomic footprinting for the HLA-B7 transgene and the endogenous H-2Kb gene. We show that the upstream region of both the transgene and the endogenous gene was extensively occupied in spleen tissue, where these genes are expressed at high levels. In contrast, no occupancy was detected in brain tissue, where expression of these genes is virtually absent. Sites exhibiting in vivo protection correspond to cis elements previously shown to bind to nuclear factors in vitro, including the constitutive enhancer region I and the interferon response element. The strongest tissue-specific protection was detected at site alpha, located downstream from the interferon response element. Site alpha bound a constitutively expressed nuclear factor(s) in vitro that exhibited an overlapping specificity which may involve a nuclear hormone receptor, RXR, and an AP-1-related factor. Site alpha was functional in vivo, as it enhanced MHC class I transcription in lymphocytes. These results show that the tissue-specific occupancy of the MHC class I regulatory sequences in vivo correlates with their expression and suggest that in vivo occupancy is controlled by a mechanism other than the mere presence of factors capable of binding to these sites. Our results suggest that a sequence present in the 660-bp upstream region in a human leukocyte antigen gene directs tissue-specific occupancy of MHC class I genes in vivo, independently of their position and copy number, illustrating a potential advantage of using a transgene for delimitation of the sequence requirement for in vivo occupancy.

Animals↗
PubMed1992

H-2RIIBP expressed from a baculovirus vector binds to multiple hormone response elements.

H-2RIIBP is a member of the nuclear hormone receptor superfamily that binds to the region II enhancer of major histocompatibility complex class I genes. Based on its homology with Drosophila XR2C/CF1, H-2RIIBP may play a role in development. By using a baculovirus expression system, a large amount of recombinant H-2RIIBP was produced. The recombinant protein accumulated in the nucleus of insect cells. A series of monoclonal antibodies reacting with the recombinant H-2RIIBP was then generated. A DNA-protein immunoprecipitation assay was developed with these antibodies, enabling the DNA-binding specificity of H-2RIIBP to be distinguished from that of an endogenous region II binding factor expressed in uninfected insect cells. We show that H-2RIIBP binds to estrogen response elements with an affinity comparable to that for the region II enhancer. H-2RIIBP also bound to some, but not all, thyroid hormone response elements and retinoic acid response elements, albeit at a lower affinity. Binding to these elements was demonstrated without exogenous addition of a ligand. The H-2RIIBP binding specificity determined by this assay was in agreement with the specificity assessed by Southwestern and gel mobility shift assays. Furthermore, methylation interference assays indicated that H-2RIIBP recognizes the conserved hormone response motif GG(T/A)CA. Taken together, these data demonstrate that H-2RIIBP is capable of binding to hormone response elements of a variety of genes. They suggest that H-2RIIBP may exert a pleiotropic function.

Amino Acid Sequence↗
PubMed1992

Heterodimerization among thyroid hormone receptor, retinoic acid receptor, retinoid X receptor, chicken ovalbumin upstream promoter transcription factor, and an endogenous liver protein.

Thyroid hormone receptor (TR) binds to DNA as a monomer, homodimer, and heterodimer with nuclear proteins. We have confirmed that the TR can heterodimerize with retinoid X receptors (RXRs)-alpha and -beta, and have found that another member of the nuclear receptor superfamily, chicken ovalbumin upstream promoter transcription factor (COUP-TF), also formed heterodimers with the TR in the context of binding to a palindromic thyroid hormone-responsive element (TREp). The interaction between COUP-TF and the TR was confirmed using specific antibodies which supershifted the COUP-TF/TR DNA complexes. The complex between the TR and the major TR heterodimerization partner in liver was unaffected by antibodies to COUP-TF and RXR beta, but was supershifted by an anti-RXR alpha antibody, indicating that the liver protein is highly related to RXR alpha. Indeed, the TR/RXR and TR/liver protein heterodimers contact the same guanidine residues in TREp. The retinoic acid receptor (RAR) also heterodimerized with COUP-TF as well as with RXR alpha, RXR beta, and the TR heterodimerization partner in liver. In contrast to its ability to heterodimerize with the TR and RAR, we did not detect heterodimers between COUP-TF and either RXR alpha, RXR beta, or the liver nuclear protein in the context of binding to the TREp. These results show that the major TR heterodimerization partner in liver is highly related to RXR alpha, but that other nuclear receptors such as COUP-TF can heterodimerize with the TR and RAR, suggesting that selective protein-protein interactions may be involved in the tissue and target gene specificities of hormone action.

Animals↗
PubMed1991

Transcription of a subset of human class II major histocompatibility complex genes is regulated by a nucleoprotein complex that contains c-fos or an antigenically related protein.

Transcriptional regulation of the human major histocompatibility complex class II genes requires at least two upstream elements, the X and Y boxes, located in the -50- to -150-base-pair region of all class II promoters. The DRA and DPB promoters contain phorbol ester-responsive elements overlapping the 3' side of their X boxes. Mutation of this sequence down-regulates the efficiency of the DRA promoter, suggesting that a positive regulator(s) binds to this site. In this report, anti-sense c-fos RNA and an anti-c-fos antibody were used to show that the product of the protooncogene c-fos or an antigenically related protein is a component of a complex that binds to the X box and is required for maximal transcription from the DRA and DPB promoters. As c-fos (or its related proteins) cannot bind alone to DNA, these results suggest that it may dimerize with other members of the JUN/AP-1 family, such as hXBP1, to participate in the activation of a subset of class II major histocompatibility complex genes.

Amino Acid Sequence↗