Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.13.3 (histidine kinase)
2,405 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Keratins are the major structural proteins of keratinocytes, which are the most abundant cell type in the mammalian epidermis. Mutations in epidermal keratin genes have been shown to cause severe blistering skin abnormalities. One such disease, epidermolytic hyperkeratosis (EHK), also known as bullous congenital ichthyosiform erythroderma, occurs as a result of mutations in highly conserved regions of keratins K1 and K10. Patients with EHK first exhibit erythroderma with severe blistering, which later is replaced by thick patches of scaly skin. To assess the effect of a mutated K1 gene on skin biology and to produce an animal model for EHK, we removed 60 residues from the 2B segment of HK1 and observed the effects of its expression in the epidermis of transgenic mice. Phenotypes of the resultant mice closely resembled those observed in the human disease, first with epidermal blisters, then later with hyperkeratotic lesions. In neonatal mice homozygous for the transgene, the skin was thicker, with an increased labeling index, and the spinous cells showed a collapse of the keratin filament network around the nuclei, suggesting that a critical concentration of the mutant HK1, over the endogenous MK1, was required to disrupt the structural integrity of the spinous cells. Additionally, footpad epithelium, which is devoid of hair follicles, showed blistering in the spinous layer, suggesting that hair follicles can stabilize or protect the epidermis from trauma. Blisters were not evident in adult mice, but instead they showed a thick, scaly hyperkeratotic skin with increased mitosis, resulting in an increased number of corneocytes and granular cells. Irregularly shaped keratohyalin granules were also observed. To date, this is the only transgenic model to show the typical morphology found in the adult form of EHK.
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PMID:A transgenic mouse model that recapitulates the clinical features of both neonatal and adult forms of the skin disease epidermolytic hyperkeratosis. 898 79

Marsupial homologs of the human chromosome 10 loci IL2RA, HK1, and PLAU have been cloned and mapped by fluorescence in situ hybridization to chromosome 1q of the tammar wallaby, Macropus eugenii. Relative distance measurements of the hybridization signals on M. eugenii chromosome 1 show that marsupial homologs of human (HSA) 10p IL2RA and 10q HK1/PLAU flank the marsupial homologs of the human 5q gene IL5 and the human 15q imprinted genes SNRPN and ZNF127. The shared synteny, therefore, does not necessarily mean that HSA 10 represents an ancestral grouping; rather, it suggests that HSA 10p and HSA 10q represent two different ancestral mammalian units which fused directly in primates and were incorporated independently into two different regions of the same chromosome in marsupials.
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PMID:Shared synteny between human chromosome 10 and chromosome 1 of the marsupial tammar wallaby, Macropus eugenii. 928 25

Multiple isoforms of type 1 hexokinase (HK1) are transcribed during spermatogenesis in the mouse, including at least three that are presumably germ cell specific: HK1-sa, HK1-sb, and HK1-sc. Each of these predicted proteins contains a common, germ cell-specific sequence that replaces the porin-binding domain found in somatic HK1. Although HK1 protein is present in mature sperm and is tyrosine phosphorylated, it is not known whether the various potential isoforms are differentially translated and localized within the developing germ cells and mature sperm. Using antipeptide antisera against unique regions of HK1-sa and HK1-sb, it was demonstrated that these isoforms were not found in pachytene spermatocytes, round spermatids, condensing spermatids, or sperm, suggesting that HK1-sa and HK1-sb are not translated during spermatogenesis. Immunoreactivity was detected in protein from round spermatids, condensing spermatids, and mature sperm using an antipeptide antiserum against the common, germ cell-specific region, suggesting that HK1-sc was the only germ cell-specific isoform present in these cells. Two-dimensional SDS-PAGE suggested that all of the sperm HK1-sc was tyrosine phosphorylated, and that the somatic HK1 isoform was not present. Immunoelectron microscopy revealed that HK1-sc was associated with the mitochondria and with the fibrous sheath of the flagellum and was found in discrete clusters in the region of the membranes of the sperm head. The unusual distribution of HK1-sc in sperm suggests novel functions, such as extramitochondrial energy production, and also demonstrates that a hexokinase without a classical porin-binding domain can localize to mitochondria.
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PMID:Targeting of a germ cell-specific type 1 hexokinase lacking a porin-binding domain to the mitochondria as well as to the head and fibrous sheath of murine spermatozoa. 945 Sep 53

Mammalian hexokinase types one and three (HK1 and HK3) are 100 kDa isozymes that phosphorylate glucose to glucose-6-phosphate. HK1 is present in most tissues but is especially prominent in brain and kidney. HK3 is less well studied, but may be most prominent in the spleen and lymphocytes. In this study, we determined the ontogeny of the expression of these isoforms in the rat. Using immunohistochemistry, we identified HK1 and HK3 immunoreactivity in the brain, heart, kidney, liver, skeletal muscle and spleen from gestational day 14 (E14) to 45 days after birth (P45). With the exception of the liver and spleen, we observed a similar age- and cell-dependent staining pattern for both isoforms in all organs studied. The brain and spleen were analyzed in more detail to identify specific regions of immunoreactivity during maturation. A transient expression of HK1 and HK3 was noted in the cell bodies of mature neurons, including layers V and VI of the cerebral cortex and the cerebellar Purkinje cells followed by localization to the white matter of the cerebrum and cerebellum. In the spleen, HK3 immunoreactivity was detected postnatally and appeared to track with the infiltration of B cells. Our demonstration of changing patterns of immunoreactivity for HK1 and HK3 in fetal and postnatal organs suggests that these HK isoforms are involved the process of development. We speculate that HK1 and HK3 share a complex interaction during development of these organs and regulate glucose metabolism at multiple levels during development.
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PMID:Developmental expression of hexokinase 1 and 3 in rats. 945 58

Nonmelanoma skin cancers (NMSC) are among the most common malignancies in the world. Typically, these neoplasms grow slowly and are comparatively indolent in their clinical behavior. The most frequent molecular alterations implicated in the pathogenesis of these neoplasms involve genes known to be regulators of cell death including p53, Ha-ras and bcl-2. In order to evaluate the significance cell death deregulation during skin carcinogenesis, we generated a transgenic mouse model (HK1.bcl-2) using the human keratin 1 promoter to target the expression of a human bcl-2 minigene to the epidermis. Transgenic HK1.bcl-2 protein was expressed at high levels specifically in the epidermis extending from the stratum basale through the stratum granulosum. The epidermis of HK1.bcl-2 mice exhibited multifocal hyperplasia without associated hyperkeratosis and aberrant expression of keratin 6. The rate of proliferation was similar in HK1.bcl-2 and control epidermis although suprabasal BrdUrd incorporating cells were present only in HK1.bcl-2 skin. Keratinocytes from the HK1.bcl-2 mice were significantly more resistant to cell death induction by U.V.-B, DMBA, and TPA, compared to control keratinocytes. Furthermore, papillomas developed at a significantly greater frequency and shorter latency in the HK1.bcl-2 mice compared to control littermates following initiation with DMBA and promotion with TPA. Together these results support a role for bcl-2 in the pathogenesis of NMSC.
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PMID:Human keratin-1.bcl-2 transgenic mice aberrantly express keratin 6, exhibit reduced sensitivity to keratinocyte cell death induction, and are susceptible to skin tumor formation. 948 76

Unique type 1 hexokinase (HK1) mRNAs are present in mouse spermatogenic cells (mHk1-s). They encode a spermatogenic cell-specific sequence region (SSR) but not the porin-binding domain (PBD) necessary for HK1 binding to porin on the outer mitochondrial membrane. This study determined the origin of the multiple Hk1-s transcripts in mouse spermatogenic cells and verified that they are translated in mouse spermatogenic cells. It also showed that a single mHk1 gene encodes the mHk1 transcripts of somatic cells and the mHk1-sa and mHk1-sb transcripts of spermatogenic cells, that alternative exons are used during mHk1 gene expression in mouse spermatogenic cells, and that mHK1-S is translated in mouse spermatogenic cells and is localized mainly with the fibrous sheath in the tail region, not with the mitochondria in the midpiece of mouse sperm.
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PMID:Mouse spermatogenic cell-specific type 1 hexokinase (mHk1-s) transcripts are expressed by alternative splicing from the mHk1 gene and the HK1-S protein is localized mainly in the sperm tail. 950 88

Skin cancer is one of the most prevalent forms of human neoplasia with a frequency approaching that of all other neoplasms combined. Given this alarming statistic, which may be further exacerbated by increased ultraviolet B irradiation from ozone depletion, it is vital that realistic, relevant model systems are developed to increase our understanding of the underlying molecular mechanisms of carcinogenesis that result in or evaluate new treatment modalities. Toward this goal, the ability to stably introduce genes into the germline of mice has greatly enhanced prospects for generation of transgenic animal models of multistage molecular carcinogenesis. Moreover, when genes are combined with regulatory sequences that target their expression to specific tissues, investigators are able to study neoplasia both in the context of living organisms and in the tissues suspected of being the targets of these genes. The epidermis is an attractive tissue for targeted gene expression; not only is it a model for epithelial diseases in general, but the accessibility of the epidermis allows easy detection of progressive pathological changes that result from transgene expression and facilitates assessment of the potential role played by environmental factors. We have developed a targeting vector based on the human keratin gene (HK1), which is expressed exclusively in the epidermis of transgenic mice, at a late stage in development and in both basal and differentiated cells. Through the use of this targeting ability, rasHa, fos, and TGF alpha transgenic mice have been developed that exhibit preneoplastic epidermal hyperplasia and hyperkeratosis, and later benign, regression prone papillomas. Together, coexpression of two oncogenes cooperated to give autonomous papillomas, which possessed the phenotypic stability to allow assessment of a third genetic event, namely loss of the p53 tumor suppressor gene, via mating with p53 knockout mice. Loss of p53 expression, however, identified a paradoxical block of papillomatogenesis. This latter result suggests that the epidermis possesses several mechanisms that can effectively compensate for the loss of important tumor suppressor functions and may have evolved to render the skin relatively resistant to the effects of environmental carcinogens.
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PMID:Multistage epidermal carcinogenesis in transgenic mice: cooperativity and paradox. 962 12

To develop an in vivo model for studying the role of the p53 tumor suppressor in skin carcinogenesis, a murine p53(172H) mutant (equivalent to human p53(175H)) was expressed in the epidermis of transgenic mice, utilizing a targeting vector based on the human keratin 1 gene (HK1.p53m). HK1.p53m mice developed normally and did not exhibit an obvious epidermal phenotype or develop spontaneous tumors. However, these mice demonstrated an increased susceptibility to a two-stage chemical carcinogenesis protocol, with the rate of formation and number of papillomas being dramatically increased as compared to non-transgenic controls. The majority of papillomas in control mice regressed after termination of 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment, whereas p53m papillomas progressed to carcinomas and metastases. In addition, more advanced malignancy, i.e., undifferentiated spindle cell carcinomas, were exclusively observed in p53m mice. Increased bromodeoxyuridine (BrdU) labeling, accompanied by decreased expression of p21, was observed in HK1.p53m papillomas. In situ examination of centrosomes in HK1.p53m papillomas also revealed marked abnormalities, with 75% of the cells containing > or = 3 centrosomes/cell, whereas centrosome numbers in papillomas from control animals remained normal. These data suggest that the accelerated tumorigenesis observed in chemically-treated p53m mice is most likely due to increased genomic instability resulting from an inhibition of G1 arrest and abnormal amplification of centrosomes.
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PMID:Expression of a p53 mutant in the epidermis of transgenic mice accelerates chemical carcinogenesis. 967 12

We previously developed a transgenic mouse model that expresses in the epidermis a murine p53172R-->H mutant (p53m) under the control of a human keratin-1-based vector (HK1.p53m). In contrast to mice with wild-type p53 and p53-knockout mice, HK1.p53m mice exhibit increased susceptibility to chemical carcinogenesis, with greatly accelerated benign papilloma formation, malignant conversion, and metastasis. In the study presented here, we examined the expression pattern of several differentiation markers and observed that p53m tumors exhibited a less differentiated phenotype than tumors elicited in non-transgenic mice. Metastasis in p53m tumors was also associated with a poorly differentiated phenotype. To determine whether genomic instability was associated with a putative gain-of-function role for this p53m, in situ examination of centrosomes was performed in HK1.p53m and equivalent p53-null papillomas. In contrast to HK1.p53m papillomas, which had centrosome abnormalities at high frequencies (75% of cells contained more than three centrosomes/cell), p53-null tumors exhibited few abnormal centrosomes (4% of cells contained more than three centrosomes/cell). To determine whether angiogenesis played a role in the rapid progression of p53m tumors, the expression of vascular endothelial growth factor, a promoter of angiogenesis, and thrombospondin-1, an inhibitor of angiogenesis, was examined in tumors derived from either p53m or p53-knockout mice. Regardless of their p53 status (wild type, p53m, p53-/-), all of the papillomas exhibited similar levels of vascular endothelial growth factor expression and decreased expression of thrombospondin-1 as did normal epidermis. In addition, tumors from different p53 genotypes showed a similar density of blood vessels. Because p53 status did not appear to play an overt role in angiogenesis, these data suggest that p53m accelerates tumorigenesis primarily by exerting a gain of function associated with genomic instability.
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PMID:Analysis of centrosome abnormalities and angiogenesis in epidermal-targeted p53172H mutant and p53-knockout mice after chemical carcinogenesis: evidence for a gain of function. 983 79

Recent evidence suggests that cholesterol sulfate may be an important second messenger involved in signaling epidermal differentiation in skin. The activity of cholesterol sulfotransferase (Ch-ST) is increased during squamous differentiation of keratinocytes and is believed to be a marker enzyme for terminal differentiation. The primary objective of this study was to examine changes in levels of cholesterol sulfate (CS) and activity of its biosynthetic enzyme, Ch-ST, during multistage carcinogenesis in mouse skin. Using SENCAR mice, we determined the activity of Ch-ST in normal epidermis, in tumor promoter-treated epidermis, in epidermis during wound healing, and in mouse skin tumors generated by initiation-promotion regimens. A single topical application of tumor promoters led to significantly elevated levels of Ch-ST activity and of CS. Epidermal Ch-ST activity was also elevated during wound healing. Dramatic increases in CS levels and in the activity of Ch-ST were found in nearly all of the papillomas and squamous cell carcinomas examined. The increased levels of CS and activity of Ch-ST in tumor promoter-treated epidermis were accompanied by increased transglutaminase-I activity. In contrast, transglutaminase I activity was not elevated in primary papillomas or squamous cell carcinomas. Finally, Ch-ST activity was significantly elevated in the epidermis of newborn HK1.ras transgenic mice, whereas transglutaminase I activity did not correlate with Ch-ST activity in these mice. These results demonstrate that diverse tumor-promoting stimuli all produce elevated CS levels and Ch-ST activity and that CS levels and Ch-ST activity were constitutively elevated in both papillomas and squamous cell carcinomas. The data also suggest a mechanism for upregulation of Ch-ST in skin tumors involving activation/upregulation of Ha-ras.
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PMID:Alterations in cholesterol sulfate and its biosynthetic enzyme during multistage carcinogenesis in mouse skin. 985 4


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