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Biomedical subjects

J M Yang

Publications and source records attributed to J M Yang.

At least 145 records · Page 8Linked to original sources
PubMed1995

Mechanisms underlying aberrant glycosylation of MUC1 mucin in breast cancer cells.

The product of the MUC1 gene, the polymorphic epithelial mucin (PEM) is aberrantly glycosylated in breast and other carcinomas, resulting in exposure of normally cryptic peptide epitopes. PEM expressed by breast cancer cells contains more sialylated O-glycans and has a lower GlcNAc content than that expressed by normal cells. The exposure of peptide epitopes is thus thought to be due to the sugar side chains being shorter on the tumour-associated mucin. To investigate possible mechanisms underlying the different pattern of glycosylation in breast cancer cells, we analysed the pathways involved in the biosynthesis of O-glycan chains of mucins in normal and cancerous mammary epithelial cells. An immortalized mammary epithelial cells line originating from normal human milk. MTSV1-7, and three human breast cancer cell lines, BT20, MCF-7 and T47D, were studied. Glycosyltransferase activities assembling, elongating and terminating O-glycan core-1 [Gal beta 1-3GalNAc alpha-R] and core-2 [GlcNac beta 1-6 (Gal beta 1-3) GalNAc alpha-R] were present in the normal mammary cell line. Many of the glycosyltransferase activities were also expressed at variable levels in breast cancer cells. However, a sialyltransferase activity (CMP-sialic acid Gal beta 1-3GalNAc alpha 3-sialyltransferase) was increased several fold in all three cancer cell lines. Moreover, mammary cancer cell lines BT20 and T47D have lost the ability to synthesize core-2, as shown by the lack of UDP-GlcNAc: Gal beta 1-3GalNAc (GlcNAc to GalNAc) beta 6-GlcNAc-transferase activity, which corresponded to the absence of the mRNA transcript. However, MCF-7 breast cancer cells expressed this enzyme. Thus, the mechanism for the exposure of peptide epitopes in BT20 and T47D cells is proposed to be the loss of core-2 branching leading to shorter, sialylated O-glycan chains. A different mechanism is proposed for MCF-7 breast cancer cells.

Amino Acid Sequence↗
PubMed1995

Involvement of phospholipase C in heat-shock-induced phosphorylation of P-glycoprotein in multidrug resistant human breast cancer cells.

The phosphorylation of P-glycoprotein has been appreciated for many years, yet little is known about the factors that initiate this post-translational modification. To determine whether the activation of P-glycoprotein phosphorylation could occur in response to cellular stress and to investigate the possible signal pathways involved, we studied the effect of heat shock on the phosphorylation of P-glycoprotein in sensitive and resistant MCF-7 human breast cancer cells. Treatment of multidrug resistant MCF-7/AdrR cells with heat shock increased the phosphorylation of P-glycoprotein. The response was not seen in the sensitive MCF-7 line, which does not express this drug transporter. Phosphorylation of P-glycoprotein induced by heat shock was not dependent on synthesis of new proteins, since phosphorylation was not inhibited by cycloheximide and the content of P-glycoprotein, as measured by immunoblotting, did not change after heat shock. The activation of P-glycoprotein phosphorylation by heat shock may be initiated through activation of phospholipase C, since heat shock stimulated the activity of this enzyme, as evidenced by increased formation of inositol trisphosphate and diacylglycerol and by phosphorylation of phospholipase C-gamma. U-73122, an inhibitor of phospholipase C and staurosporine, an inhibitor of protein kinase C, both decreased the heat-shock-induced phosphorylation of P-glycoprotein. These results suggest that heat shock induces phosphorylation of P-glycoprotein through the activation of the phospholipase C/protein kinase C pathway.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Simultaneous determination of moricizine and its sulphoxidation metabolites in biological fluids by high-performance liquid chromatography.

A simultaneous assay for moricizine, its two sulphoxidation metabolites, moricizine sulphoxide and moricizine sulphone, using high-performance liquid chromatography (HPLC) is described. The drug and metabolites and clozapine (internal standard) in biological fluids were extracted using pentanesulphonic acid into diethyl ether. The ethereal extract was evaporated to dryness and the residue was redissolved in the mobile phase (methanol-water-triethylamine, 65:35:0.5, v/v). The analyses were performed on a microBondapak reversed-phase C18 column housed in a Waters Z-module, linked to a C18 pre-column, with a run-time of 12 min. The retention times were 2.7, 3.5, 6.2 and 9.7 min for moricizine sulphone, moricizine sulphoxide, moricizine and clozapine, respectively. The recovery of the compounds from plasma ranged from 89.9% for the sulphoxide to 98.1% for clozapine. The limits of detection of the assay for moricizine, moricizine sulphoxide and moricizine sulphone were 20, 10 and 5 ng/ml, respectively.

Animals↗
PubMed1995

Synthesis of O-glycan core 3: characterization of UDP-GlcNAc: GalNAc-R beta 3-N-acetyl-glucosaminyltransferase activity from colonic mucosal tissues and lack of the activity in human cancer cell lines.

UDP-GlcNAc: GalNAc-R beta 3-GlcNAc-transferase (core 3 beta 3-GlcNAc-T, where GlcNAc is N-acetyl-D-glucosamine, GalNAc is N-acetyl-D-galactosamine and T is transferase) is expressed in a tissue-specific fashion and is high in normal colonic tissue, but downregulated in colon cancer. To further study the control of this enzyme, we examined the activity in pig, rat and human colonic tissues, and several human cancer cell lines. The enzyme was difficult to solubilize by detergents and was extremely unstable in the solubilized form. Using synthetic derivatives of the GalNAc-R substrate, we showed that the specificity of the enzyme in normal rat and human colonic mucosa requires all the substituents of the GalNAc-sugar ring of substrates for maximal activity. Core 3 beta 3-GlcNAc-T was significantly influenced by the structure of the aglycon group. None of the inactive substrate derivatives could inhibit the activity. N-Iodoacetamido-galactosamine alpha-benzyl was a weak substrate and significantly inhibited the incorporation of GLcNAc into GalNAc alpha-benzyl by human colonic homogenates. Surprisingly, none of the colonic cancer cell lines or any other cancer and leukaemia cells examined exhibited detectable activity of the enzyme, although a number of other glycosyltransferase activities involved in O-glycan biosynthesis were active. Mixing experiments did not reveal an endogenous inhibitor in HL60 cells or an activator of core 3 beta 3-GlcNAc-T in human colonic mucosa. Thus, the lack of core 3 beta 3-GlcNAc-T in human colonic mucosa. Thus, the lack of core 3 beta 3-GlcNAc-T activity in cancer cell lines may be due to cell transformation or cell culturing.

Amino Acid Sequence↗
PubMed1995

Mini-catheter used for bladder drainage following stress-incontinence surgery and the factors relating to drainage failure.

OBJECTIVES: To determine the most effective length for the mini-catheter and to discuss factors relating to drainage failure. METHODS: Prospective study of a No. 8 silastic feeding tube for bladder drainage omits the necessity of additional catheterization for measuring residual urine. This two-part study in which 146 patients took part, first, determined the suitable length for insertions for the perforated portion and the imperforated portion; then, gauged the effectiveness of the mini-catheter with desired proportions. RESULTS: Drainage is better when the imperforated portion is at least 5 cm in length (p = 0.0129). The length of the perforated portion, on the other hand, has less impact of the resultant drainage provided that its length does not exceed 5 cm. Beyond this length, an obstruction often occurs. There were 2 obstructions (1.3%) induced by blood clot as well as 9 patients (5.8%) who suffered from one, or more, complications attributed to the mini-catheter for reasons other than the length of insertion. CONCLUSIONS: When care is taken in creating a mini-catheter of the proper proportions, it offers many advantages and very few complications to gynecologists and patients alike.

Drainage↗
PubMed1995

Relationship between acute fetal distress and maternal-placental-fetal circulations in severe preeclampsia.

BACKGROUND: Hypoxic complications are thought to be the result of vascular lesions in the maternal-placental or fetal-placental circulation, with a resultant decrease in blood flow. This study was designed 1) to explore what kind of pathophysiological changes occur in the maternal-placental-fetal circulations associated with acute fetal distress, and 2) to determine whether umbilical velocimetry can be used as a predictor of acute hypoxia in severe preeclampsia. METHODS: Eighty-nine cases of severe preeclampsia, who had Doppler ultrasonography, maternal blood chemistry and hematogram examinations all performed within two days of delivery or fetal death, were studied. RESULTS: According to the absence or presence of acute fetal distress as determined by the fetal heart rate pattern, patients were divided into two groups: distress group and non-distress group. There was no significant difference between the two groups in maternal general status. However, patients in the distress group had a significantly shorter gestation age on admission and at delivery (p < 0.00001). In the distress group, the perinatal outcome was poor. Newborns in the distress group had, significantly, a lower birthweight, and a higher incidence of SGA, 1-min Apgar scores of less than 7, and fetal acidosis (pH < 7.2) (p < 0.001). Doppler ultrasonography also showed a significantly higher incidence of abnormal umbilical artery Doppler waveforms in the distress group (p < 0.05). However, there was no difference between the two groups in the uterine artery Doppler velocimetry. Maternal blood chemistry and hematogram examinations revealed significantly higher blood levels of hemoglobin, hematocrit, blood urea nitrogen, and creatinine but lower levels of total protein and albumin in the distress group. An abnormal umbilical artery SD ratio (> 95th centile) as a predictor of acute fetal compromise, judged by the incidence of abnormal fetal heart tracing mandating emergency delivery, 1-minute Apgar scores of less than 7, 5-minute Apgar scores of less than 7, and a pH value for the umbilical arterial blood of less than 7.2, had a sensitivity of 40.5-75%, specificity of 71.8-80%, positive predictive value of 12.5-75%, and negative predictive value of 64.5-98.4%. CONCLUSION: In severe preeclampsia, early onset of disease superimposed with maternal hemoconcentration might initiate an acute insult and predispose the fetus to acute hypoxia.

Adult↗
PubMed1995

Preeclampsia in multiple pregnancy.

BACKGROUND: Preeclampsia is one of the most common pregnancy-induced complications, and results in a large number of maternal deaths. How pregnancy incites or aggravates hypertension remains unresolved; despite decades of intensive research directed to hypertensive disorders, they remain among the most important unresolved problems in obstetrics. The incidence of preeclampsia is increased in multiple pregnancies, and several preeclampsia-related fetal risks may be particularly hazardous to the babies of multiple gestations. METHODS: The records of 561 women with multiple pregnancies delivered consecutively at Mackay Memorial Hospital were reviewed retrospectively. Thirteen mild cases and 39 severe cases of preeclampsia in multiple pregnancies were compared with 52 control cases of multiple pregnancies without preeclampsia, but matched for maternal age and parity. The categories for comparison included parity, gestational age, time of onset of preeclampsia, route of delivery, mean birth weight, growth discordancy, maternal complications, neonatal morbidity and mortality. RESULTS: The incidence of preeclampsia in our consecutive series of 561 multiple pregnancies was 9.3% compared with 1.8% in singleton pregnancies (p < 0.0001). In primiparas with multiple pregnancies, the incidence of preeclampsia was 12.2% compared with 6.2% (p < 0.05) in multiparas. Breech presentation was the most common indication for Cesarean section in all groups. The preeclamptic group had a significantly higher rate of Cesarean section compared with the control group (p < 0.006), with prolonged labor and fetal distress were the two main reasons for this difference. Severe preeclamptic patients had babies with significantly lower mean birth weights (p < 0.05), higher incidence of intrauterine growth retardation (p < 0.025) and neonatal respiratory distress syndrome (p < 0.0008) compared with those of the control group. All seven cases with maternal complications were in the severe preeclamptic group. CONCLUSIONS: An unfavorable perinatal outcome was found to be associated with severe, but not with mild, preeclampsia in multiple pregnancies.

Female↗
PubMed1995

What kind of maternal factor might predict poor perinatal outcome in severe preeclampsia?: a study based on doppler velocimetry.

BACKGROUND: Umbilical artery Doppler velocimetry has been used as an important perinatal tool to identify fetal compromise. However, the fact that it is both expensive and time-consuming makes it not always available. This study was a search for any maternal serum laboratory test which might be much simpler and easier than Doppler velocimetry, and still determining the perinatal outcome in severe preeclampsia. METHODS: Forty-seven patients with severe preeclampsia were enrolled in this study. Doppler velocimetry of umbilical artery, maternal serum biochemistry and hematological tests were all performed within two days prior to delivery or fetal death. RESULTS: By choosing a maternal hematocrit (Hct) of greater than 44% as the cutoff value, a significantly higher incidence of adverse perinatal events was noted in patients with abnormal value than those with normal value. Abnormal Hct level as a predictor of adverse perinatal outcome had a sensitivity of 50.0%, a specificity of 84.2%, a positive predictive value of 53.3% and a negative predictive value of 63.8%. CONCLUSIONS: This study found that elevated maternal Hct (> 44%) levels might indicate a condition of hemoconcentration with reduced placental perfusion in severely preeclamptic patients. Hct level can serve as a clinically useful predictor of adverse perinatal outcome.

Adult↗
PubMed1994

Inhibition of protein synthesis in insect cells by baculovirus-expressed heme-regulated eIF-2 alpha kinase.

To study further the regulation of the heme-regulated eIF-2 alpha kinase (HRI), we have produced functional wild type HRI using the baculovirus expression system. The amount of recombinant HRI protein expressed in insect cells is approximately 10 times higher than levels in reticulocytes. Baculovirus-expressed HRI (BV-HRI) is indistinguishable from HRI purified from rabbit reticulocytes. It is active both as an autokinase and an eIF-2 alpha kinase. BV-HRI is regulated by heme in vitro as well as in intact insect cells. Coexpression of the wild type HRI with the inactive K199R HRI, S51A eIF-2 alpha, or interleukin-1 beta (IL-1 beta) results in diminished expression of these proteins. Expression of wild type HRI also results in severe inhibition of general protein synthesis in Sf9 cells when compared with cells expressing K199R HRI or IL-beta. In addition, the guanine nucleotide exchange activity of eIF-2B is suppressed in Sf9 cells expressing wild type HRI but not in cells expressing the K199R HRI or IL-1 beta. Furthermore, expression of wild type HRI is increased by coexpression with the nonphosphorylatable S51A eIF-2 alpha or by the addition of hemin, which inhibits HRI activity. These results provide evidence that translational regulation by phosphorylation of eIF-2 alpha and sequestration of eIF-2B can operate in insect cells.

Animals↗
PubMed1994

Characteristics of P388/VMDRC.04, a simple, sensitive model for studying P-glycoprotein antagonists.

Cross-resistance to chemotherapeutic drugs is a significant problem in the treatment of patients with cancer. The discovery that this phenomenon is associated with the overexpression of a membrane glycoprotein, P-glycoprotein, which acts as a drug efflux pump, has provided a new target for drug development. To develop a model for identifying new compounds which can block the function of P-glycoprotein, we infected P388 mouse leukemic cells with a retrovirus containing a cloned human MDR1 complementary DNA. The new cell line, P388/VMDRC.04, incorporated and overexpressed the human gene as evidenced by Southern blots, increased mRNA and protein synthesis, and recognition by the MRK16 monoclonal antibody. P388/VMDRC.04 was cross-resistant to colchicine, vincristine, and doxorubicin, and the degree of resistance correlated with a reduction in cellular drug accumulation. Unlike many cell lines selected for resistance by growth in increasing concentrations of drug for prolonged periods of time, these cells did not show alternative mechanisms of resistance such as increased synthesis of glutathione or alterations in topoisomerase II. In addition, the sensitivity of P388/VMDRC.04 cells was completely restored by cyclosporin A and trans-flupenthixol. P388/VMDRC.04 cells were subcloned and 10 clones were picked for in vivo evaluation. One subclone grew similarly to parental cells in female BALB/c x DBA/2 F1 mice and showed no responsiveness to therapeutic doses of vincristine or etoposide. The combination of vincristine with cyclosporin A significantly increased the survival of mice inoculated with P388/VMDRC.04 cells. The availability of a cell line that displays the MDR phenotype, overexpresses human P-glycoprotein, but does not contain alterations in at least two well-defined alternative mechanisms of resistance, and that can be grown in simple animal models should facilitate the development of new agents active against this form of chemotherapeutic drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Pax-6 is first expressed in a region of ectoderm anterior to the early neural plate: implications for stepwise determination of the lens.

The Pax-6 gene encodes a DNA-binding transcription factor essential to normal development of the mammalian eye. We have found that in the chick embryo, the Pax-6 gene is first expressed in a crescent-shaped region of future head ectoderm that adjoins the anterior margin of the early neural plate. As development proceeds, this region of Pax-6-positive ectoderm becomes divided into two bilateral domains. Upon contact with the optic vesicles, portions of these domains give rise to the invaginating lens placodes, which contain high levels of Pax-6 mRNA. As with mouse, rat, and zebrafish, chick Pax-6 is also expressed in the neural epithelium of the forebrain and optic vesicles. However, our results indicate that the onset of expression in the prospective head ectoderm occurs at a substantially earlier stage. Experiments involving unilateral ablation of the anterior neural plate indicate that contact with an optic vesicle is not required to maintain expression of Pax-6 in the ectoderm. Experiments in which optic vesicles have been displaced from their normal location further suggest that positioning of Pax-6 domains in the head ectoderm is independent of neighboring optic vesicles. Homozygous defects in the mouse and rat Pax-6 gene are known to cause complete failure of lens formation at the optic vesicle stage and block subsequent development of the optic cup. Our results raise the possibility that Pax-6 may be involved in the early establishment of lens-competent regions within the head ectoderm.

Amino Acid Sequence↗
PubMed1994

A new beta-adrenoceptor blocking agent derived from dehydrozingerone.

1. Dehydrozingeronolol (DZPN; 0.1, 0.5, 1.0 mg/kg, i.v.) produced a dose-dependent bradycardia response and a sustained pressor action in urethane-anesthetized normotensive rats. DZPN inhibited the tachycardia effects by (-)isoproterenol, but had no blocking effect on the arterial pressor responses induced by phenylephrine. 2. In in vitro study, DZPN antagonized (-)isoproterenol-induced positive chronotropic effects in guinea-pig isolated right atria and relaxation responses in rat isolated uterus horns. 3. DZPN causes mild direct cardiac depression at high concentrations without intrinsic sympathomimetic activity (ISA). 4. The order of potency of beta-adrenoceptor antagonists in competing for the [3H]dihydroalprenolol binding sites was (-)propranolol >> DZPN > or = atenolol.

Adrenergic beta-Antagonists↗
PubMed1994

Autonomic and sensory cardiovascular activities of nonivamide: intrathecal administration of clonidine.

The effects of nonivamide on the cardiovascular system were examined and compared with the effects of substance P (SP) in rats. Intravenous (i.v.) injection (10 micrograms/kg) of nonivamide produced triphasic pressure responses (A; depressor, B; pressor, and C; depressor) and biphasic bradycardia responses (f; fast bradycardia and s; slow bradycardia). IA injection (10 micrograms/kg) into the epigastric artery caused hypotension and mild tachycardia. The effects of atropine, vagotomy, SP antagonist, propranolol, and clonidine on these responses were examined and mechanisms responsible for the nonivamide-induced responses are postulated as follows. A and f are due to vagal reflex resulting from the excitation of afferent sensory neurons in the heart and are parasympathetic efferent effects from the nucleus solitarius. B is involved in sympathetic activation, partly caused by the release of SP in the spinal cord. C is due to the vasodilatory effect of SP released from perivascular stores. s was diminished by vagotomy and is due to the bradycardiac effect of acetylcholine, released by SP, from cardiac stores. The activation of the autonomic system is inhibited by clonidine and involved in the wide spectrum of nonivamide-induced cardiovascular effects.

Animals↗
PubMed1994

Desensitization of nicotine-stimulated 86Rb+ efflux from mouse brain synaptosomes.

The desensitization of nicotine-stimulated 86Rb+ efflux from synaptosomes prepared from C57BL/6 mouse brain was investigated. Nicotine stimulated a saturable, concentration-dependent efflux of 86Rb+ from synaptosomes (EC50 = 0.60 microM), but the response decreased with time of exposure to nicotine. The rate of decrease of the response (desensitization) increased as the nicotine concentration was increased (EC50 = 0.35 microM; maximal rate of desensitization = 1.1 min-1). Desensitization of nicotine-stimulated 86Rb+ efflux was also observed when synaptosomes were exposed to low (1-200 nM) concentrations of nicotine that caused little or no stimulation of efflux (EC50 = 13 nM). The rate of desensitization observed with low nicotine concentrations (0.30 min-1) was less than that measured at stimulating concentrations. Desensitization was not fully reversible for synaptosomes exposed to nicotine concentrations between 10 nM and 10 microM: Only 60-40% of the control response was regained after a 10-min washout period. The kinetics of functional desensitization were compared with the kinetics of [3H]nicotine binding. [3H]Nicotine binding to midbrain particulate fractions displayed both a fast and a slow phase. The EC50 values for these two phases were 2.6 and 14 nM, respectively. Data obtained from functional desensitization and ligand binding experiments were analyzed using a two-state model. The kinetic constants obtained from the analyses of these two processes were very similar. Overall, the results suggest that nicotinic receptor function measured with ion flux desensitizes when exposed to either stimulating or nonstimulating concentrations of nicotine. In addition, the kinetic properties calculated for the functional desensitization are comparable to those for [3H]nicotine binding.

Animals↗
PubMed1994

Alterations of O-glycan biosynthesis in human colon cancer tissues.

Human colon cancer is associated with antigenic and structural changes in mucin-type carbohydrate chains (O-glycans). To elucidate the control of the biosynthesis of these O-glycans is colon cancer, we have studied glycosyltransferase and sulphotransferase activities involved in the assembly of elongated O-glycan structures. We analysed homogenates prepared from cancer tissue, adjacent normal and distal normal tissue from 20 patients. Several transferase activities showed pronounced changes in cancer tissue. The changes correlate with previous findings of a loss of O-glycans in cancer mucins, but did not always correlate with levels of Tn, sialyl-Tn, T and Lex antigens in homogenates or with the differentiation status and Duke's stages of the cancer tissue or the patient's blood type, sex and age. UDP-GlcNAc: Gal NAc-R beta 3-N-acetylglucosaminyltransferase (where GlcNAc is N-acetyl-D-glucosamine and GalNAc is N-acetyl-D-galactosamine) synthesizing O-glycan core 3, GlcNAc beta 1-3GalNAc-, CMP-sialic acid: GalNAc-peptide alpha 6-sialyltransferase synthesizing the sialyl-Tn antigen and sulphotransferase activities towards O-glycan core 1, Gal beta 1-3GalNAc-, were found to be decreased in cancer. UDP-GlcNAc: Gal beta 1-3GalNAc beta 6-N-acetylglucosaminyltransferase was also decreased in cancer concomitant with a loss of the ability to synthesize the I antigen and core 4, GlcNAc beta 1-6(GlcNAc beta 1-3) GalNAc-, CMP-sialic acid: Gal beta 1-3GalNAc-R alpha 3-sialyltransferase and GDP-fucose: Gal beta-R alpha 2-fucosyltransferase, synthesizing the blood group H determinant, were found to be 4- and 3- to 8-fold increased, respectively, in cancer compared to normal tissue. The data suggest that the biosynthesis of antigens and mucin-bound O-glycan structures in colon cancer is subject to complex control mechanisms.

Adult↗
PubMed1994

Mutations in the H1 and 1A domains in the keratin 1 gene in epidermolytic hyperkeratosis.

In the autosomal dominant disorder epidermolytic hyperkeratosis, the structural integrity of the keratin intermediate filaments is altered in the suprabasal layers of the epidermis. We and others have used genetic linkage studies and mutation analysis to establish that single amino acid substitutions in either the keratin 1 or keratin 10 chains can cause epidermolytic hyperkeratosis. However, a larger database of mutations is required to better understand the relationship between specific mutations in these keratin chains and their effect on keratin filament structure. A larger database will also provide a catalog that may be useful for genetic counseling purposes. In this paper, we report the identification of three new mutations of the keratin 1 chain of epidermolytic hyperkeratosis probands in highly conserved residues in the H1 or beginning of the 1A rod domain segments. These correspond to regions involved in molecular overlaps between neighboring molecules in keratin filaments. Using an in vitro assay, synthetic peptides bearing these substitutions show diminished capacity to disassemble preformed filaments in vitro in comparison to the wild type peptides. Moreover, analyses of all mutations in epidermolytic hyperkeratosis known to date demonstrate remarkable clustering in the molecular overlap region. We conclude that non-conservative substitutions in the overlap region are likely to interfere with normal keratin filament structure and function, leading to pathology.

Amino Acid Sequence↗
PubMed1994

Structure and organization of the human transglutaminase 3 gene: evolutionary relationship to the transglutaminase family.

The human haploid genome contains a family of at least five different transglutaminases that are differentially expressed in time- and tissue-specific ways. Of these, transglutaminase 3 (TGase3) is unusual in that it is a pro-enzyme requiring activation by proteolysis. To date it is known to be expressed only in terminally differentiating epidermal and hair follicle keratinocytes. In this paper we show that it is encoded by a gene (TGM3) of 42.8 kbp containing 13 exons. In the course of isolation of genomic clones for the TGM3 gene, we also found clones encoding the widely expressed tissue or TGase2 enzyme, perhaps due to high degrees of sequence homology. The structure of the TGM2 gene has not yet been reported. Our incomplete data suggest its exon/intron organization is very similar to that of TGM3. Although the common intron splice points of all members of the transglutaminase gene family have been conserved, the TGM3 and TGM2 genes, and the gene for the subplasma membrane transglutaminase-like protein band 4.2, lack two introns found in the TGM1 and factor XIIIa genes, and the exact intron splice point of another intron is shifted with respect to that of the TGM1 and factor XIIIa genes. Based on sequence homologies and gene structures, the data support a phylogenic tree in which the TGM2 and TGM3 genes belong on a branch distinct from other transglutaminases.

Base Sequence↗