Biomedical subjects

S Nagpal

Publications and source records attributed to S Nagpal.

At least 37 records · Page 2Linked to original sources

PubMed1999

Secretion of glutathione S-transferase isoforms in the seminiferous tubular fluid, tissue distribution and sex steroid binding by rat GSTM1.

The seminiferous tubular fluid (STF) provides the microenvironment necessary for spermatogenesis in the adluminal compartment of the seminiferous tubule (ST), primarily through secretions of the Sertoli cell. Earlier studies from this laboratory demonstrated the presence of glutathione S-transferase (GST) in STF collected from adult rat testis and in the spent media of ST cultures. This study describes the cellular source, isoform composition and possible function of GSTs in the STF. The major GST isoforms present in STF in vivo share extensive N-terminal similarity with rat GSTM1 (rGSTM1), rGSTM2, rGSTM3 and rGST-Alpha. Molecular masses of rGSTM2, rGSTM3 and rGST-Alpha from liver and testis sources were similar, unlike STF-GSTM1, which was larger by 325 Da than its liver counterpart. Peptide digest analysis profiles on reverse-phase HPLC between liver and STF isoforms were identical, and N-terminal sequences of selected peptides obtained by digestion of the various isoforms were closely similar. The above results confirmed close structural similarity between liver and STF-GST isoforms. Active synthesis and secretion of GSTs by the STs were evident from recovery of radiolabelled GST from the spent media of ST cultures. Analysis of secreted GST isoforms showed that GST-Alpha was not secreted by the STs in vitro, whereas there was an induction of GST-Pi secretion. Detection of immunostainable GST-Mu in Sertoli cells in vitro and during different stages of the seminiferous epithelium in vivo, coupled with the recovery of radiolabelled GST from Sertoli cell-culture media, provided evidence for Sertoli cells as secretors of GST. In addition, STF of 'Sertoli cell only' animals showed no change in the profile of GST isoform secretion, thereby confirming Sertoli cells as prime GST secretors. Non-recovery of [35S]methionine-labelled GSTs from germ cell culture supernatants, but their presence in germ cell lysates, confirm the ability of the germ cells to synthesize, but not to release, GSTs. Functionally, STF-GSTM1 appeared to serve as a steroid-binding protein by its ability to bind to testosterone and oestradiol, two important hormones in the ST that are essential for spermatogenesis, with binding constants of <9.8x10(-7) M for testosterone and 9x10(-6) M for oestradiol respectively.

Animals↗

PubMed1999

Treatment of Guillain-Barré syndrome: a cost-effectiveness analysis.

Acute Guillain-Barré syndrome is the most common cause of neuromuscular paralysis. Plasma exchange and intravenous immune globulin (IV IgG) are both effective treatments for this condition and the purpose of this report was to compare the cost-effectiveness of these two modalities. A MEDLINE search was performed to identify randomized studies that compared the use of IV IgG and plasma exchange for treatment of acute Guillain-Barré syndrome to determine if one modality was more effective and/or safer for the management of this condition. A decision analysis was structured around the alternatives facing neurologists who must choose a treatment regimen for patients diagnosed with acute Guillain-Barré syndrome who require active therapy. Cost information was obtained directly from product manufacturers and hospital sources. Two head-to-head trials comparing the effectiveness of plasma exchange and IV IgG for treatment of acute Guillain-Barré syndrome determined that there was insufficient evidence to suggest one therapy was more effective than the other; therefore, a cost minimization analysis was performed. The costs per patient of plasma exchange and IV IgG for the treatment of acute Guillain-Barré syndrome were $6,204 and $10,165, respectively. A sensitivity analysis determined the model was sensitive to the cost of IV IgG. The cost savings per patient treatment for the use of plasma exchange varied from $304 to $6,625 depending on the IV IgG product selected. Plasma exchange and IV IgG are both effective treatments for Guillain-Barré syndrome. However, our analysis determined plasma exchange on average was almost $4,000 less costly per patient than IV IgG. Further research is required to determine the impact of patient and physician preferences on the treatment of this disorder.

Canada↗

PubMed1999

Identification of the AP1-antagonism domain of retinoic acid receptors.

Retinoids are therapeutically effective in the treatment of psoriasis, photoaging, acne, and certain cancers. Some of the therapeutic actions of retinoids can be ascribed to retinoic acid receptor (RAR)-mediated antagonism of AP1-dependent gene expression. The increased activity of transcription factor AP1, a complex of oncoproteins Jun and Fos, is associated with cell growth and proliferation. Retinoids, on the other hand, inhibit cell proliferation and affect differentiation, activities that possibly stem from an antagonism of AP1-mediated gene expression by RARs. To gain insight into the molecular mechanism of RAR-AP1 interaction, we have identified the regions of the RAR required for AP1 antagonism. We demonstrate that the AP1 antagonism domain of RAR is a complex of the core of the DNA binding domain and the hydrophobic zipper region. Further, both monomeric RAR and RAR-RXR heterodimers inhibit the expression of an AP1 reporter. CREB binding protein (CBP) has been described as a cofactor for AP1, various nuclear hormone receptor proteins including RARs, and certain other transcription factors and is required for their transactivation properties. Therefore, CBP has been proposed as a common limiting cofactor that can account for inhibition of AP1-dependent gene expression by RARs. Interestingly, however, our results along with previously reported observations suggest that in addition to CBP, there may be other limiting cofactor(s) responsible for mutual transrepression of RAR and AP1.

Binding Sites↗

PubMed1999

Novel approaches for the treatment of psoriasis.

Psoriasis is a common skin disease affecting approximately 2% of the population. For those who contract the disease it is usually recurrent and sometimes very debilitating. The cause of psoriasis is unknown, although it appears to be an autoimmune disease with a likelihood for genetic predisposition. Past topical treatments such as emollients, coal tar and dithranol have been messy, cosmetically unacceptable and of low efficacy, while systemic therapies such as methotrexate, cyclosporin and acitretin have suffered from significant side effects. New therapies based on medicinal chemistry and an increased understanding of psoriasis have brought us closer to the goal of safe and efficacious treatment of the disease. The authors review some of these new topical and systemic therapies currently in use or in development.

Journal Article↗

PubMed1999

Cell type and gene-specific activity of the retinoid inverse agonist AGN 193109: divergent effects from agonist at retinoic acid receptor gamma in human keratinocytes.

Retinoids are important regulators of epithelial differentiation. AGN 193109 is a high-affinity antagonist and inverse agonist for the nuclear retinoic acid receptors (RARs). Paradoxically, both AGN 193109 and retinoid agonists inhibit the expression of the differentiation marker MRP-8 in normal human keratinocytes (NHKs). TTNPB, an RAR agonist, and AGN 193109 mutually antagonize MRP-8 inhibition at both mRNA and protein levels. We find that this antagonism, which is greatest at an AGN 193109:TTNPB ratio of about 10:1, is absent when either compound is in significant excess. The potent RARalpha-specific agonist, AGN 193836, has no effect on MRP-8 regulation. These data indicate that inverse agonists and agonists suppress MRP-8 in NHKs through RARgamma using distinct and mutually inhibitory mechanisms. The activity of AGN 193109 on MRP-8 is cell type specific. In differentiating ECE16-1 cervical cells, TTNPB inhibits while AGN 193109 induces MRP-8 mRNA levels. The effect of AGN 193109 on genes inhibited by retinoid agonists in NHKs is also selective; expression of the differentiation markers transglutaminase 1 and keratin 6 is not down-regulated by AGN 193109 whereas stromelysin-1 expression is suppressed. These results show a complex gene and cell context-specific interplay between agonist and inverse agonist for the regulation of gene expression.

Calcium-Binding Proteins↗

PubMed1999

Venous thromboembolism prophylaxis after total hip or knee arthroplasty: a survey of Canadian orthopedic surgeons.

OBJECTIVE: To determine the pharmacologic and physical modalities used by orthopedic surgeons in Canada to prevent venous thromboembolism (deep venous thrombosis and pulmonary embolism) after total hip or knee arthroplasty. DESIGN: Mail survey sent to all members of the Canadian Orthopaedic Association. SETTING: A nation-wide study. METHODS: A total of 828 questionnaires, designed to identify the type and frequency of prophylaxis against venous thromboembolism that were used after hip and knee arthroplasty were mailed to orthopedic surgeons. OUTCOME MEASURES: Demographic data and the frequency and type of thromboprophylaxis. RESULTS: Of the 828 surveys mailed 445 (54%) were returned, and 397 were included in this analysis. Of the respondents, 97% used prophylaxis routinely for patients who undergo total hip or knee arthroplasty. Three of the 397 (0.8%) did not use any method ofprophylaxis. Warfarin was the most common agent used (46%), followed by low-molecular-weight heparin (LMWH) (36%). Combination therapy with both mechanical and pharmacologic methods were used in 39% of patients. Objective screening tests were not frequently performed before discharge. Extended prophylaxis beyond the duration of hospitalization was used by 36% of physicians. CONCLUSION: Prophylaxis for venous thromboembolism with warfarin or LMWH has become standard care after total hip or knee arthroplasty in Canada.

Anticoagulants↗

PubMed1998

Identification and characterization of a retinoid-induced class II tumor suppressor/growth regulatory gene.

Retinoids, synthetic and natural analogs of retinoic acid, exhibit potent growth inhibitory and cell differentiation activities that account for their beneficial effects in treating hyperproliferative diseases such as psoriasis, actinic keratosis, and certain neoplasias. Tazarotene is a synthetic retinoid that is used in the clinic for the treatment of psoriasis. To better understand the mechanism of retinoid action in the treatment of hyperproliferative diseases, we used a long-range differential display-PCR to isolate retinoid-responsive genes from primary human keratinocytes. We have identified a cDNA, tazarotene-induced gene 3 (TIG3; Retinoic Acid Receptor Responder 3) showing significant homology to the class II tumor suppressor gene, H-rev 107. Tazarotene treatment increases TIG3 expression in primary human keratinocytes and in vivo in psoriatic lesions. Increased TIG3 expression is correlated with decreased proliferation. TIG3 is expressed in a number of tissues, and expression is reduced in cancer cell lines and some primary tumors. In breast cancer cell lines, retinoid-dependent TIG3 induction is observed in lines that are growth suppressed by retinoids but not in nonresponsive lines. Transient over-expression of TIG3 in T47D or Chinese hamster ovary cells inhibits colony expansion. Finally, studies in 293 cells expressing TIG3 linked to an inducible promoter demonstrated decreased proliferation with increased TIG3 levels. These studies suggest that TIG3 may be a growth regulator that mediates some of the growth suppressive effects of retinoids.

Amino Acid Sequence↗

PubMed1998

Regions of association between the alpha and the beta subunit of the gastric H,K-ATPase.

A binding and a yeast two-hybrid analysis were carried out on the gastric H,K-ATPase to determine interactive regions of the extracytoplasmic domains of the alpha and beta subunits of this P type ATPase. Wheat germ agglutinin fractionation of fluorescein 5-maleimide-labeled tryptic fragments of detergent-solubilized H, K-ATPase showed that a fragment Leu855 to Arg922 of the alpha subunit was bound to the beta subunit. The yeast two-hybrid system showed that the region containing only a part of the seventh transmembrane segment, the loop, and part of the eighth transmembrane segment was capable of giving positive interaction signals with the ectodomain of the beta subunit. The sequence in the extracytoplasmic loop close to the eighth transmembrane segment, namely Arg898 to Thr928, was identified as being the site of interaction using this method. We deduced that the sequence Arg898 to Arg922 in the alpha subunit has strong interaction with the extracytoplasmic domain of the beta subunit. Again, using yeast two-hybrid analysis, two different sequences in the beta subunit Gln64 to Asn130 and Ala156 to Arg188 were identified as association domains in the extracytoplasmic sequence of the beta subunit. These data enable identification of major associative regions of the alpha-beta subunits of the H,K-ATPase.

Amino Acid Sequence↗

PubMed1998

Studies on glutathione S-transferases important for sperm function: evidence of catalytic activity-independent functions.

Our earlier studies reported the identification of a rat testicular protein of 24 kDa with significant similarity at the N-terminus with Mu class glutathione S-transferases (GSTs). Treatment of goat sperm with antisera against this protein identified immunoreactive sites on the spermatozoa and inhibited in vitro fertilization of goat oocytes by the antibody-treated sperm. The above observations indicated the presence of GST-like molecule(s) important for fertility related events on goat spermatozoa. In this study, we report the purification of goat sperm GSTs (GSP1) which were purified by glutathione affinity chromatography and were enzymically active towards 1-chloro-2,4,-dinitrobenzene, a general GST substrate, and ethacrynic acid, a substrate for Pi class GSTs. GSP1 resolved into three major components on reverse-phase HPLC: peaks 1 and 2 with molecular masses of 26.5 kDa and peak 3 with a molecular mass of 25.5 kDa, as determined by SDS/PAGE. Multiple attempts to obtain N-terminal sequences of the first two peaks failed, indicating N-terminal block; however, they reacted to specific anti-Mu-GST antisera on Western blots and ELISA, and not to anti-Pi-GST antisera, which provides evidence for the presence of Mu-GST-reactive sites on peaks 1 and 2. The third component showed 80% N-terminal similarity with human and rat GSTP1-1 over an overlap of 15 amino acids, and reacted to anti-Pi-specific antisera in ELISA. Sperm labelled with antibodies against a 10-mer and an 11-mer peptide, designed from the N-terminal sequences of Mu and Pi class GSTs respectively, showed the presence of both Mu- and Pi-GST on goat sperm surface at distinct cellular domains. Selective inhibition of Pi class GST by the Pi-specific antisera, either at 0 h or at 3 h after initiation of sperm capacitation, leads to a reduction in fertilization rates. In contrast, the inhibition of Mu class GST by specific antisera at 0 h does not inhibit fertilization, although such treatment at 3 h after the initiation of capacitation reduces fertilization rates. The results indicate that both Pi- and Mu-GSTs are involved in fertilization, but the Mu-GST sites essential for fertilization are exposed only after 3 h of capacitation. The enzymic activity of GSP1 or live spermatozoa is not inhibited by the two antisera. The inability of the antibodies to cause such inhibition indicates that the reduction in fertilization rates and acrosome reaction caused by the antibodies is through a mechanism which does not interfere with the catalytic activity of the molecule. Therefore we established the presence of Pi and Mu class GST on goat sperm, their localization and their possible function in fertility-related events.

Animals↗

PubMed1998

Vitamin A and regulation of gene expression.

The biologically active form of vitamin A, retinoic acid, and its synthetic analogs exhibit potent anti-proliferative normalization of differentiation and anti-inflammatory activities, which appear to account for their therapeutic effects in hyperproliferative and inflammatory diseases, such as acne, psoriasis, photoaging and neoplasias. These therapeutic effects are achieved by their ability to regulate complex programs of gene expression in target cells by binding to nuclear receptors, which are ligand-dependent transcription factors. This article reviews retinoid regulated genes and recently identified mechanisms which play important roles in the regulation of transcription by retinoids.

Acetyltransferases↗

PubMed1997

Helix-loop-helix motif in GnRH associated peptide is critical for negative regulation of prolactin secretion.

The GnRH associated prolactin inhibiting factor (GAP) reveals the signature sequence associated with the helix-loop-helix structural motif. A number of different peptide fragments of GAP were designed, synthesized and analysed by circular dichroism and by an in vivo assay for prolactin secretion inhibiting activity. Peptides corresponding to the two individual alpha-helices and a 44-residue peptide comprising the entire helix-loop-helix motif show significant helical propensity in circular dichroism spectra. However, a peptide corresponding to the loop sequence shows no helical propensity. Albeit, the peptide corresponding to helix-loop-helix motif was found to inhibit prolactin secretion and augment circulating levels of gonadotropins in the in vivo assay; other shorter peptides did not show such activity. The activity profile of the 44-residue peptide was biphasic and very similar to that of the recombinant GAP. Thus, the prolactin inhibiting activity of this factor is defined by its helix-loop-helix motif as in the case of the transcription factors of developmental genes. The structural features of a homology-based model of GAP in complex with E47, a ubiquitous HLH-type developmental gene regulator, are consistent with the structural requirements of the negative regulation of transcription by helix-loop-helix proteins.

Amino Acid Sequence↗

PubMed1997

Retinoic acid receptor-nuclear factor-interleukin 6 antagonism. A novel mechanism of retinoid-dependent inhibition of a keratinocyte hyperproliferative differentiation marker.

Retinoids inhibit the expression of migration inhibitory factor-related protein-8 (MRP-8), a marker of hyperproliferative or abnormal keratinocyte differentiation, in a retinoic acid receptor (RAR)-dependent manner in various cell culture systems. MRP-8 expression is also down-regulated in vivo in psoriatic lesions after topical application of an anti-psoriatic RARbeta/gamma-selective synthetic retinoid, tazarotene. We demonstrate that an MRP-8 promoter linked to a chloramphenicol acetyltransferase reporter (MRP8CAT) faithfully replicates the differentiation-specific regulation of the endogenous keratinocyte MRP-8 gene. Further, interferon gamma and serum-induced expression of MRP8CAT is inhibited by retinoid receptors in a ligand-dependent manner. We also show that NF-IL6 acts as a transcriptional enhancer of MRP-8, and that RARs inhibit MRP8CAT by inhibiting the enhancer action of nuclear factor-interleukin-6 (NF-IL6). The NF-IL6 antagonism function of RAR is a complex of the core of the DNA binding domain and the hydrophobic zipper region. This manuscript identifies NF-IL6 as another transcription factor, in addition to AP1, whose activity is inhibited by RAR in a ligand-dependent manner. The interdiction of NF-IL6-dependent signal transduction pathway by RARs may explain some of the therapeutic effects of retinoids in inflammatory and proliferative diseases.

Antigens, Differentiation↗

PubMed1997

Ligand-induced receptor dimerization may be critical for signal transduction by choriogonadotropin.

A mechanism of signal transduction by human choriogonadotropin (hCG) has been proposed. Competitive inhibition of the binding of hCG to its receptor by the serine protease inhibitors led to the identification of local structural homology of an extracellular region of the receptor with the reactive site loop of chymotrypsin inhibitor. Synthetic peptides from the extracellular domain of luteinizing hormone-choriogonadotropin (LH/CG) receptor, rationally designed on the basis of this homology, were found to affect hormone-receptor binding and bioactivity. A receptor peptide incorporating one complete structural unit of the leucine-rich repeats motif of the extracellular domain of the receptor significantly increased hCG-receptor binding in a dose-dependent manner. However, the testosterone production in a Leydig cell bioassay was inhibited in the presence of this peptide. The agonistic effect on the hCG-receptor binding and the antagonistic effect on the testosterone production of a receptor peptide suggests the possibility of more than one quasi-equivalent receptor-binding site on the hormone. Hormone-induced receptor oligomerization may therefore be involved in the mechanism of signal transduction by hCG.

Amino Acid Sequence↗

PubMed1997

Tazarotene-induced gene 2 (TIG2), a novel retinoid-responsive gene in skin.

Retinoids exert their biologic effects through two families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which belong to the superfamily of steroid/thyroid hormone nuclear receptors. By using a subtraction hybridization approach, we have identified a cDNA sequence TIG2 (Tazarotene-induced gene 2), whose expression is up-regulated by the treatment of skin raft cultures by an RAR beta/gamma-selective anti-psoriatic synthetic retinoid tazarotene [AGN 190168/ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl] nicotinate]. The retinoid-mediated up-regulation in the expression of TIG2 was confirmed by Northern blot analysis. Upon sequencing, TIG2 was found to be a cDNA whose complete sequence was not in the GenBank and EMBL data bases. The TIG2 cDNA is 830 bp long and encodes a putative protein product of 164 amino acids. TIG2 is neither expressed nor induced by tazarotene in primary keratinocyte and fibroblast cultures. Thus, TIG2 is expressed and induced by tazarotene only when keratinocytes and fibroblasts form a tissue-like 3-dimensional structure. We further demonstrate that RAR-specific retinoids increase TIG2 mRNA levels. In contrast, neither RXR-specific retinoids nor 1,25-dihydroxyvitamin D3 increased TIG2 levels. Finally, we demonstrate that TIG2 is expressed at high levels in nonlesional psoriatic skin but at lower levels in the psoriatic lesion and that its expression is up-regulated in psoriatic lesions after topical application of tazarotene.

Administration, Topical↗

PubMed1997

Retinoid antagonism of NF-IL6: insight into the mechanism of antiproliferative effects of retinoids in Kaposi's sarcoma.

All-trans-retinoic acid (RA) is active in the treatment of Kaposi's sarcoma (KS), and retinoids inhibit KS cell growth in vitro. To understand the mechanism of retinoid action in KS, we studied the expression of autocrine growth factors of KS cells after RA treatment. We demonstrate that RA and its synthetic analogs inhibit the proliferation of KS cells by inhibiting the mRNA and protein levels of interleukin-6 (IL-6), an autocrine growth factor for KS cells. We further demonstrate that nuclear retinoid receptors (RA receptors [RARs] and retinoid X receptors [RXRs]) inhibit IL-6 promoter action by antagonizing the enhancer action of NF-IL6, a basic domain leucine zipper transcription factor belonging to the family of CAAT enhancer binding proteins. Furthermore, RARs and RXRs do not bind in vitro to an NF-IL6 binding site. However, the secondary folded structure of the DNA binding domain of RAR and RXR is obligatory for inhibiting NF-IL6 activity. Thus, NF-IL6 is a potential therapeutic target for the treatment of KS. Finally, using receptor-selective synthetic retinoids, we demonstrate that NF-IL6 antagonism and transactivation are separable functions of RAR alpha, thus indicating that synthetic retinoids with properties of NF-IL6 antagonism but lacking transactivation capabilities can be synthesized. Such retinoids might increase therapeutic potential in KS.

CCAAT-Enhancer-Binding Proteins↗

PubMed1997

Molecular mechanisms of tazarotene action in psoriasis.

Psoriasis is a chronic immune-mediated disease that is characterized by the hyperproliferation and abnormal differentiation of keratinocytes and by inflammation. The epidermal changes associated with psoriasis may be due to the infiltration of inflammatory T lymphocytes and the release of cytokines in response to antigenic stimulation. Tazarotene is a retinoic acid receptor-specific retinoid with demonstrated efficacy in the topical treatment of psoriasis. Tazarotene down-regulates markers of keratinocyte differentiation, keratinocyte proliferation, and inflammation. The drug also up-regulates three novel genes TIG-1 (tazarotene-induced gene-1), TIG-2, and TIG-3, which may mediate an antiproliferative effect. The effect of tazarotene on these markers is probably a direct effect on gene expression rather than an indirect effect associated with disease improvement.

Cell Differentiation↗

PubMed1996

Identification and functional separation of retinoic acid receptor neutral antagonists and inverse agonists.

Inverse agonists are ligands that are capable of repressing basal receptor activity in the absence of an agonist. We have designed a series of C-1-substituted acetylenic retinoids that exhibit potent antagonism of retinoic acid receptor (RAR)-mediated transactivation. Comparison of these related retinoid antagonists for their ability to repress basal RAR transcriptional activity demonstrates that the identity of the C-1 substituent differentiates these ligands into two groups: RAR inverse agonists and neutral antagonists. We show that treatment of cultured human keratinocytes with a RAR inverse agonist, but not a RAR neutral antagonist, leads to the repression of the serum-induced differentiation marker MRP-8. While RAR-selective agonists also repress expression of MRP-8, cotreatment with a RAR inverse agonist and a RAR agonist results in a mutual repression of their individual inhibitory activities, indicating the distinct modes of action of these two disparate retinoids in modulating MRP-8 expression. Our data indicate that RARs, like beta2-adrenoreceptors, are sensitive to inverse agonists and that this new class of retinoids will provide insight into the molecular mechanisms of RAR function in skin and other responsive tissues.

Antigens, Differentiation↗

PubMed1996

Tazarotene-induced gene 1 (TIG1), a novel retinoic acid receptor-responsive gene in skin.

Retinoids exert their effect through ligand-dependent transcription factors, retinoic acid receptors (RARalpha, beta, and gamma) and retinoid X receptor (RXRalpha, beta, and gamma), which belong to the superfamily of steroid/thyroid/vitamin D3, nuclear receptors. Using a subtraction hybridization approach, we have identified a cDNA sequence, Tazarotene Induced Gene 1 (TIG1), which is highly upregulated in skin raft cultures by an RARbeta/gamma -selective retinoid AGN 190168 (tazarotene/ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl]nicotinate), which is effective in the treatment of psoriasis. The retinoid-mediated upregulation in the expression of TIG1 was confirmed by Southern and Northern analyses. Upon sequencing, TIG1 was found to be a novel cDNA which encodes a protein of 228 amino acids whose sequence suggests that is a transmembrane protein with a small N-terminal intracellular region, a single membrane-spanning hydrophobic region, and a large C-terminal extracellular region containing a glycosylation signal. We demonstrate that TIG1 is also upregulated by AGN 190168 in skin raft cultures prepared from psoriatic fibroblasts and normal keratinocytes and in primary fibroblast and keratinocyte cultures. We also show that TIG1 is upregulated by retinoic acid receptor but not by retinoid X receptor-specific synthetic retinoids. Finally, we demonstrate that TIG1 is induced by AGN 190168 in psoriatic lesions during the course of clinical treatment of the disease.

Amino Acid Sequence↗