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Human homologue of murine tumor rejection antigen gp96: 5'-regulatory and coding regions and relationship to stress-induced proteins.

ABSTRACT: Cell-surface glycoproteins of 96 kDa (gp96) have been implicated in immunogenicity of methylcholanthrene-induced mouse sarcomas in syngeneic hosts. In view of the potential immunogenicity of gp96-related molecules in human tumors, we have defined the 5'-regulatory and complete coding regions of a human gp96 transcript. The 5'-regulatory region contains an imperfect heat shock element apart from other regulatory sequences. The amino acid sequence of human gp96 is 96% homologous to its murine counterpart and genes for the two molecules show significant homology between untranslated regions. Comparison of gp96 sequences to other sequences in DNA and protein data bases indicates significant homology with the stress proteins 94-kDa glucose-regulated protein (grp94) and 108-kDa heat shock protein (hsp108) and 99-kDa endoplasmic reticular protein (ERp99). These molecules are either identical or represent a family of closely related molecules. With regard to their role in tumor immunity, it needs to be determined whether gp96 molecules are tumor antigens per se or whether they serve as carriers of other immunogenic moieties.

SUBMITTER: Maki RG

PROVIDER: S-EPMC54386 | biostudies-other | 1990 Aug

REPOSITORIES: biostudies-other

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Human homologue of murine tumor rejection antigen gp96: 5'-regulatory and coding regions and relationship to stress-induced proteins.

Maki R G RG Old L J LJ Srivastava P K PK

Proceedings of the National Academy of Sciences of the United States of America 19900801 15

Cell-surface glycoproteins of 96 kDa (gp96) have been implicated in immunogenicity of methylcholanthrene-induced mouse sarcomas in syngeneic hosts. In view of the potential immunogenicity of gp96-related molecules in human tumors, we have defined the 5'-regulatory and complete coding regions of a human gp96 transcript. The 5'-regulatory region contains an imperfect heat shock element apart from other regulatory sequences. The amino acid sequence of human gp96 is 96% homologous to its murine coun ...[more]

PMID: 2377606

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Project description:The vertebrate immune response is mediated through highly adaptive, quickly evolving cell surface receptors, the major histocompatibility complex (MHC). MHC molecules bind and present a diverse array of pathogenic molecules and trigger a cascade of defenses. Use of MHC variation as a marker for population health has also evolved quickly following advances in sequencing methods. We applied a combination of traditional and next generation sequencing methodology to characterize coding (peptide binding region) and regulatory (proximal promoter) sequence variation in MHC Class II DQA and DQB genes between estuarine and coastal populations of the bottlenose dolphin, Tursiops truncatus, an apex predator whose health status is indicative of anthropogenic impacts on the ecosystem. The coding regions had 10 alleles each at DQA and DQB; the promoters had 6 and 7 alleles at DQA and DQB, respectively with variation within key regulatory motifs. Positive selection was observed for the coding regions of both genes while both coding and promoter regions exhibited geographic differences in allele composition that likely indicates diversifying selection across habitats. Most notable was the discovery of a complete duplication of a 14-bp T-box motif in the DQA promoter. Four class II promoter regions (DQA, DQB, DRA, DRB) were characterized in species from four cetacean families (Delphinidae, Monodontidae, Lipotidae, and Physeteridae) and revealed substantial promoter structural diversity across this order. Peptide binding regions may not be the only source of adaptive potential within cetacean MHC for responding to pathogenic threats. These findings are the first analysis of cetacean MHC regulatory motifs, which may divulge unique immunogenetic strategies among cetaceans and reveal how MHC transcriptional control continues to evolve. The combined MHC regulatory and coding data provide new genetic context for distinct vulnerability profiles between coastal and estuarine populations, which are key concerns for health and risk management.

Project description:To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products) in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear) depends on changes in the specific values of local response coefficients (gains) distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear, and depending on the level of local gains, presence of gain-changing events, and degree of feedforward gene activation, this region can appear as superlinear, sublinear, or even J-shaped. The general dose response transition proposed here was further examined in a complex anti-electrophilic stress pathway, which involves multiple genes, enzymes, and metabolic reactions. This work would help biologists and especially toxicologists to better assess and predict the cellular impact brought about by biological stressors.

Dataset Information

Human homologue of murine tumor rejection antigen gp96: 5'-regulatory and coding regions and relationship to stress-induced proteins.

Publications

Human homologue of murine tumor rejection antigen gp96: 5'-regulatory and coding regions and relationship to stress-induced proteins.

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