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PubMed1996

Analysis of differential gene regulation in adequate versus inadequate secretory-phase endometrial complementary deoxyribonucleic acid populations from the rhesus monkey.

The ability to create artificial menstrual cycles in the rhesus monkey provides a model for studies on the regulation of genes and gene networks by estradiol or progesterone (P) in the primate endometrium. This model allowed us to create both a normal level of secretory phase P or an inadequate level of secretory phase P, i.e. endometria that cannot support implantation. The objective of our present study focused on PCR analyses of genes for several factors that are believed to be important in the proper maturation of the endometrium. Complementary DNA (cDNA) populations were prepared from endometria harvested on day 13 (peak E level), days 21-23 of an adequate secretory phase (PcDNA) and days 21-23 of an inadequate secretory phase (IcDNA). Although placental protein 14, leukemia inhibitory factor and 17-beta hydroxysteroid dehydrogenase displayed highly upregulated levels in PcDNA (P-activated genes), there was little or no up-regulation in IcDNA. Transforming growth factor-beta 2 and its receptor and insulin growth factor-I and its receptor were up-regulated in PcDNA, whereas little or no expression was observed in IcDNA. Regulators of the cell cycle and transcription, such as retinoblastoma, c-fos, and c-jun genes, were also greatly underexpressed in IcDNA compared with PcDNA. Interestingly, one gene that we studied, keratinocyte growth factor, that was up-regulated by P (peak E levels vs. PcDNA) was more highly expressed in IcDNA. This latter result suggests that low levels of circulating P are sufficient for expression of this gene, whereas high sustained P levels result in an autologous down-regulation. These data show that the regulation of genes that may play pivotal roles in endometrial maturation are differentially expressed in IcDNA vs. PcDNA and may, in part, characterize improper endometrial maturation.

17-Hydroxysteroid Dehydrogenases↗

PubMed1999

Merbarone, a catalytic inhibitor of DNA topoisomerase II, induces apoptosis in CEM cells through activation of ICE/CED-3-like protease.

Merbarone (5-[N-phenyl carboxamido]-2-thiobarbituric acid) is an anticancer drug that inhibits the catalytic activity of DNA topoisomerase II (topo II) without damaging DNA or stabilizing DNA-topo II cleavable complexes. Although the cytotoxicity of the complex-stabilizing DNA-topo II inhibitors such as VP-16 (etoposide) has been partially elucidated, the cytotoxicity of merbarone is poorly understood. Here, we report that merbarone induces programmed cell death or apoptosis in human leukemic CEM cells, characterized by internucleosomal DNA cleavage and nuclear condensation. Treatment of CEM cells with apoptosis-inducing concentrations of merbarone caused activation of c-Jun NH2-terminal kinase/stress-activated protein kinase, c-jun gene induction, activation of caspase-3/CPP32-like protease but not caspase-1, and the proteolytic cleavage of poly(ADP-ribose) polymerase. Treatment of CEM cells with a potent inhibitor of caspases, Z-Asp-2. 6-dichlorobenzoyloxymethyl-ketone, inhibited merbarone-induced caspase-3/CPP32-like activity and apoptosis in a dose-dependent manner. These results indicate that the catalytic inhibition of topo II by merbarone leads to apoptotic cell death through a caspase-3-like protease-dependent mechanism. These results further suggest that c-Jun and c-Jun NH2-terminal kinase/stress-activated protein kinase signaling may be involved in the cytotoxicity of merbarone.

Apoptosis↗

PubMed1994

Oncogene activation and tumor suppressor gene inactivation during multistage mouse skin carcinogenesis.

The mouse skin multistage model of carcinogenesis is an ideal system in which to study questions related to the timing of oncogene activation and inactivation of tumor suppressor genes. A number of laboratories have shown that an early event associated with chemical initiation of mouse skin tumors involves activation of the Harvey-ras oncogene. To approach the question of timing of loss of tumor suppressor genes in skin carcinogenesis, we have utilized a model system developed by Kulesz-Martin in which cloned mouse keratinocytes were initiated with DMBA and variant clones with benign or malignant phenotypes were developed. We have generated somatic cell hybrids between the parental clone and the variants to study the potential loss of tumor suppressor activity during the progression of cells from the initiated to benign and to the malignant phenotypes. Somatic cell hybrids generated between the parental, normal cell strain (i.e., 291) and a malignant cell variant (i.e., 05), that produces moderately differentiated squamous cell carcinomas (SCCs), failed to produce tumors indicating tumor suppressor activity in the 291 cells. The 291 cells and a benign papilloma producing variant (i.e., 09) were able to partially suppress in hybrids the tumorigenicity of another malignant cell line (i.e., 03) which produces poorly-differentiated SCCs. Suppression of 03 tumorigenicity by the benign tumor cell, 09, was less than that seen with the normal cell, 291. These results indicated two potentially different suppressor activities were inactivated during progression of normal 291 to malignant 03 cells. We have also obtained evidence that constitutive AP-1 activity plays a role in the maintenance of the malignant phenotype of SCC cell lines. Two different SCC cell lines, 308 10Gy5 and PDV, demonstrate constitutive AP-1 activity. To examine the role of this activity in malignant progression, we stably expressed a transactivation deletion mutant of the human c-jun gene in these cell lines. Expression of this mutant c-jun protein blocked transcriptional transactivation of AP-1 responsive reporter CAT constructs driven by jun, human collagenase, and the mouse stromelysin promoters. These malignant cells were not only inhibited in their AP-1 transactivation response, but also in their ability to form SCCs upon s.c. injection into athymic nude mice. These results support the idea that inhibition of AP-1-mediated transcriptional transactivation is in some cases sufficient to suppress the tumorigenic phenotype of malignant mouse epidermal cells.

Animals↗

PubMed1994

Stable expression of a c-JUN deletion mutant in two malignant mouse epidermal cell lines blocks tumor formation in nude mice.

We have stably expressed a trans-activation suppressing deletion mutant of the human c-jun gene (TAM-67) in the malignant mouse epidermal cell lines 10Gy5 and PDV. Expression of the p26 mJUN protein blocked both constitutive and inducible transcriptional trans-activation of several AP-1 responsive reporter chloramphenicol acetyltransferase constructs. p26 mJUN was able to block both 12-O-tetradecanoylphorbol-13-acetate (TPA) and okadaic acid induced expression of the mouse stromelysin gene in 10Gy5 cells and TPA induced expression of the urokinase-type plasminogen activator gene in PDV cells as determined by Northern analyses. Both genes contain TPA response elements in their promoter regions and are known to be AP-1 responsive. The presence of p26 mJUN in nuclear extracts, as determined by Western blotting, did not detectably alter the DNA binding activity of endogenous AP-1 as determined by gel shift analysis with an oligonucleotide containing a single high affinity AP-1 binding site. UV cross-linking studies coupled with Western analyses identified DNA bound cJUN but not mJUN in nuclear extracts of stably transfected cell lines, suggesting that the mutant JUN protein may exert some of its antioncogenic effects in malignant mouse epidermal cells by a mechanism(s) not involving DNA binding. Malignant mouse epidermal cells which stably expressed the mutant JUN protein were not only inhibited in their AP-1 trans-activation response, but also in their ability to form s.c. tumors in nude mice. These results indicate that inhibition of AP-1 mediated transcriptional trans-activation alone can be sufficient to suppress the tumorigenic phenotype in a subset of malignant mouse epidermal cells.

Animals↗

PubMed2001

c-jun cooperates with SV40 T-antigen to sustain MMP-2 expression in immortalized cells.

The c-jun gene is a major regulator of proliferative and stress responses of both normal and transformed cells. In general, during immortalization/transformation c-jun cooperates with oncogenic signals rather than acting as an oncogene itself. Here we report a novel example of this cooperation, the requirement for c-jun to sustain expression of the matrix metalloproteinase-2 (MMP-2) gene in cells immortalized by SV40 large T-antigen (TAg). MMP-2 encodes a type IV collagenase that is secreted by cells within normal and tumor microenvironments. We used wild-type and c-jun null primary and TAg-immortalized mouse embryonic fibroblasts (mEFs) to investigate the importance of c-jun for the regulation of this activity, and observed that c-jun is essential for MMP-2 expression in immortalized but not primary mEFs. This finding directly demonstrates a cooperative interaction of c-jun with an oncogene, and suggests that TAg dependent immortalization/transformation may require other c-Jun/AP-1-dependent genes.

Animals↗

PubMed1991

Uncoupled changes in the expression of the jun family members during myeloid cell differentiation.

The differentiation into macrophages of the U937 and HL60 human cell lines induced by 4 beta-phorbol 12-myristate 13-acetate (PMA) was accompanied by induction of the expression of the proto-oncogenes c-jun, jun B and jun D. However, expression of the three jun genes was regulated differently during induction of cell differentiation in both U937 and HL60 cells, with the three jun family members being expressed distinctly at different stages of cell differentiation. Whereas jun B transcription was strongly stimulated following treatment with PMA for 30 min, jun D mRNA levels were only increased 6 h after PMA treatment and the content of c-jun mRNA was elevated maximally only 24 h after PMA treatment. The rapid induction of the jun B mRNA level suggests a putative role for this proto-oncogene in the early triggering step of U937 and HL60 cell differentiation induced by PMA. Interestingly, a weak induction of jun B and jun D mRNA levels, but no induction of the c-jun mRNA level, was detected during Me2SO-induced granulocytic HL60 differentiation. These data suggest a different role for each jun proto-oncogene in regulating gene activity and that different transcriptional complexes involving distinct jun proto-oncogenes can be formed during macrophage and granulocytic differentiation.

Blotting, Northern↗

PubMed1990

Cadmium induces transcription of proto-oncogenes c-jun and c-myc in rat L6 myoblasts.

The effect of cadmium on the expression of oncogenes c-jun, c-fos, and c-myc was studied by exposing L6J1 myoblast cultures to different doses of cadmium chloride and then analyzing the abundance of oncogene transcripts. Cadmium induced a transient accumulation of c-jun and c-myc mRNA with maximum expression at 2-4 h. At the same time, the level of c-fos transcripts remained below the detection level. Both the c-fos and c-jun genes could. However, be induced by treating the myoblasts with insulin. Cadmium induction of c-jun and c-myc mRNA occurred in a concentration-dependent manner with maximum stimulation at 5-10 microM. In the presence of cycloheximide, c-jun and c-myc genes were superinduced by the addition of cadmium. Under these conditions there was also a marked increase in c-fos transcripts. Induction of c-myc and c-jun by cadmium and c-fos by a combination of cadmium and cycloheximide could be abolished by blocking transcription with actinomycin D. The cadmium-induced increase in c-jun and c-myc mRNA was enhanced in myoblasts stably transfected with a mouse c-fos gene under a metallothionein promoter. Our present data suggest that cadmium has the potential to deregulate the expression of several important oncogenes.

Animals↗

PubMed1995

Retinoic acid inhibits estrogen-induced uterine stromal and myometrial cell proliferation.

Retinoic acid, a potent natural derivative of vitamin A, influences proliferation in many cell types. However, little is known about the role of retinoic acid in estrogen-induced proliferation in normal physiological systems. In this study we sought to determine if in vivo administration of retinoic acid influences the proliferation of a normal estrogen target tissue, the immature rat uterus. The results indicate that treatment of animals with 30 mg/kg all-trans-retinoic acid for 3 days before 17 beta-estradiol (E2) administration diminishes DNA synthesis and cell division by approximately 50% in uterine stromal and myometrial cells. Luminal epithelial cell proliferation is not inhibited, indicating that the antiproliferative effects of all-trans-retinoic acid treatment are cell type-specific. The inhibition is retinoid-specific and fully reversible 1 week after discontinuing all-trans-retinoic acid treatment. The inhibitory effect of all-trans-retinoic acid is not due to a change in E2 receptor levels assessed by ligand binding. E2 induction of c-jun, a gene expressed primarily in myometrial cells, is unaffected in retinoid-treated animals. This is the first demonstration that retinoic acid inhibits estrogen-induced proliferation of uterine stromal and myometrial cells in a physiological setting.

Animals↗

PubMed1995

The kinetics of induction of Hox1.6 and C-jun mRNA during three different ways of inducing differentiation in teratocarcinoma F9 cells.

Changes in Hox1.6 and c-jun gene expression were examined upon F9 cell differentiation that was induced by three independent methods: a drug treatment with retinoic acid (RA), that with sodium butyrate (NaB), and a genetic approach using the ts mutant. To obtain further information on the mechanism of teratocarcinoma cell differentiation we have examined the kinetics of the induction of Hox1.6 and c-jun mRNA whose gene products have been demonstrated to have specific roles in gene regulation. Expression of Hox1.6 mRNA was induced more rapidly than c-jun mRNA by all the above three inducing methods. Furthermore, protein synthesis was not required for the induction of Hox1.6 mRNA as well as of c-jun mRNA synthesis in all three methods. The data suggested that the transcriptional increase in the Hox1.6 mRNA was a primary response and could play an important role in F9 cell differentiation.

Butyrates↗

PubMed2005

DNA microarray analysis of gene expression in iris and ciliary body of rat eyes with endotoxin-induced uveitis.

The purposes of this study are to determine the genes that are up- or down-regulated in eyes with endotoxin-induced uveitis (EIU) by an oligonucleotide microarray system, and to determine the temporal and spatial changes in expression of selected genes that show strong up-regulation. EIU was induced by a footpad injection of lipopolysaccharide (LPS) in male Lewis rats. The expression of genes in the iris-ciliary body (ICB) at 2, 6, 12, and 24 hr after LPS injection was determined by oligonucleotide microarray analyses and compared to that in control rats. The microarray displayed 9911 genes and expressed sequence tags (ESTs). Cluster analysis was performed for highly up-regulated genes. Selected genes for cytokines (interleukin (IL)-1 beta and IL-6), chemokines (RANTES), and immediate early genes (Jun B, c-Fos, and c-Jun) were also studied by real-time polymerase chain reaction (PCR). Immunohistochemical studies were performed to localize the protein expression of some immediate early gene products. After LPS injection, the expression of 1930 genes were increased or decreased over 2-folds compared with normal controls by 24 hr. One hundred and seventeen genes were up-regulated over 10-fold, and these were classified into five clusters with similar expression pattern. The immediate early genes and transcription factors genes were included in one cluster of up-regulated genes peaking at 2 hr after the LPS injection. The expressions of cytokines, chemokines, and adhesion molecules were highly up-regulated. Real-time PCR analyses for selected genes showed similar expression changes as detected by the microarray analyses. Jun B immunoreactivity was found in the ICB cells at 3 and 6 hr after LPS injection. Gene expression changes after LPS injection were profiled by using an oligonucleotide microarray system. Our data suggest that the immediate early genes, such as Jun B, play an important role in inducing the inflammatory-related genes in the ICB.

Animals↗

PubMed1994

Induction of multiple immediate early genes in rat hypothalamic paraventricular nucleus after stress.

We have previously demonstrated that stress causes a rapid and transient elevation in the expression of the immediate early genes (IEGs) c-fos and the members of the jun gene family in the brain. Here we demonstrate the effect of stress on the expression of fra-1, fra-2 and recently characterized IEGs encoding zinc finger containing proteins. Capsaicin-induced stress caused a rapid and transient induction of NGFI-A, NGFI-B, fra-2 and TIS11 in the hypothalamic paraventricular nucleus. The NGFI-A mRNA levels were also slightly increased in the cerebral cortex and striatum. The expression of fra-1, NGFI-C, egr-3 and Nurr1 did not show any change. The time course of the induction of NGFI-A, NGFI-B, fra-2 and TIS11 was similar to that previously observed with c-fos and the members of the jun family. The present results suggest that NGFI-A, NGFI-B, fra-2 and TIS11 mediate some of the stress-induced changes of the PVN at the level of gene expression. Although the genes of the NGFI/egr family encode structurally similar proteins, they seem to be regulated differentially and thus have diverse roles in regulating gene expression in the brain.

Animals↗

PubMed1990

Differential expression of jun and fos genes during differentiation of mouse P19 embryonal carcinoma cells.

The jun and fos gene families encode DNA binding proteins involved in transcriptional regulation of genes containing a TPA responsive element (TRE). To study their role in gene regulation during early mammalian development, expression and transcription regulatory properties of their gene products were investigated during retinoic acid (RA) induced differentiation of P19 embryonal carcinoma (EC) cells. Our results show, that c-jun is expressed at low but detectable levels in undifferentiated P19 EC cells and at elevated levels in its RA differentiated derivatives, corresponding with increased expression of Jun and TRE binding activity. Jun D is constitutively expressed at constant levels in both undifferentiated and differentiated P19 cells, while jun B and c-fos are not expressed. Addition of TPA to undifferentiated P19 cells does not result in induction of c-jun, jun B and c-fos, while these genes are transiently induced in RA-differentiated P19 cells. In addition, TPA treatment resulted in expression of Fos and Jun protein in RA-differentiated, but not in undifferentiated P19 cells. Addition of TPA to P19 EC cells expressing low levels of TRE binding proteins is neither followed by transcriptional activation of the TRE reporter gene nor by induction of c-jun, previously shown to be autoregulated by its own gene product. By contrast, in P19 cells differentiated by RA that contain elevated levels of TRE binding proteins, TRE dependent transcription is enhanced upon TPA treatment.

Animals↗

PubMed1993

Modulation of expression of endogenous collagenase and collagen genes by electroporation: possible involvement of Ca2+ and protein kinase C.

We have investigated the effect of electroporation on the expression of collagen alpha 1(I), collagenase, c-fos and c-jun genes in human dermal fibroblasts (HDF), human smooth muscle cells (HSMC) and HeLa cells. Collagenase and collagen mRNA levels were respectively increased and decreased in a voltage-dependent manner in HDF harvested 2 days after a sham electroporation. These effects were still observed 10 days after electroporation. Similar effects occurred in electroporated HSMC. Neither collagen nor collagenase mRNAs were detected in control or electroporated HeLa cells. c-fos and c-jun mRNA levels were also increased in electroporated HDF, HSMC and HeLa cells harvested 1 h after plating. This suggests that factor AP1 (fos/jun) could mediate the up-regulation of collagenase expression in electroporated HDF and HSMC. When electroporation of HDF was performed in the presence of H7, an inhibitor of protein kinase C, no increase in collagenase mRNA level was observed, suggesting that protein kinase C might be involved in the transduction of the effect. All the effects reported were also suppressed when cells were electroporated in a medium containing EGTA, suggesting that Ca2+ might mediate the transduction of this effect.

Aluminum↗

PubMed1999

E1A + cHa-ras transformed rat embryo fibroblast cells are characterized by high and constitutive DNA binding activities of AP-1 dimers with significantly altered composition.

Transcription factors of the AP-1/ATF family, including c-Fos, c-Jun, and ATF-2, play an important role in the regulation of cell proliferation and differentiation, and changes in their levels and/or activities may contribute to oncogenesis. We analyzed the alterations of AP-1/ATF transcription factors upon immortalization and transformation in a panel of cell lines derived from rat embryo fibroblast (REF) cells. The tumorigenic E1A + cHa-ras cells are characterized by high and constitutive DNA binding activities of AP-1, in contrast to nontransformed cells and the E1A cells. The expression of c-fos and c-jun genes was affected differently by the oncogenic transformation. By using antibodies to c-Jun and c-Fos proteins in electrophoretic mobility shift assays (EMSA), we showed that E1A + cHa-ras transformants did not contain c-Fos under any condition of cell cultivation and growth factor stimulation, whereas c-Jun was constitutively upregulated. In the absence of c-fos gene expression, c-Fos protein appears to be replaced by proteins of Fos family (Fra-1) and ATF family (ATF-2 and ATFa). To determine the possible mechanisms of c-fos downregulation in E1A + cHa-ras transformants we have obtained populations of geneticin-resistant clones containing integrated reporter construct -711fos-CAT and its mutants in serum-responsive element (SRE) and cAMP-responsive element (CRE). Data obtained show that the mutations within the SRE lead to a manifold activation of fos-CAT expression. This allows to suggest that c-fos downregulation in E1A + cHa-ras transformants is provided by a negative control mediated through the SRE regulatory region. The profound differences in regulation and composition of transcription factors of the AP-1 family probably play a pivotal role in the transformation of REF cells by E1A and cHa-ras oncogenes.

Adenovirus E1A Proteins↗

PubMed1991

Different patterns of gene expression in ras-resistant and ras-sensitive cells.

We have shown previously that nontumorigenic NIH 3T3 cells can be made tumorigenic and metastatic by transfection and expression of activated ras, whereas in LTA cells, which are tumorigenic but nonmetastatic, the degree of malignancy is not altered by ras. To investigate possible mechanisms of natural ras resistance, we compared the expression patterns of several genes thought to be involved in ras-induced metastatic progression in LTA (ras-resistant) and NIH 3T3 (ras-sensitive) cells, before and after constitutive expression of transfected T24-H-ras. We examined the expression of the nuclear "early-response" genes jun and fos and the "tumor-suppressor" retinoblastoma (Rb) gene, as well as genes involved in invasion (major excreted protein [MEP], tissue inhibitor of metalloproteinases [TIMP]), and cell adhesion (secreted phosphoprotein 1 [SPP1; also known as osteopontin]). We found distinct differences in both the basal and ras-induced levels of expression of most of these genes in LTA versus NIH 3T3 cells. High levels of MEP and low levels of TIMP were induced in ras-transfected NIH 3T3 cells, whereas LTA cells showed intermediate levels of MEP and high levels of TIMP that were only marginally affected by the expression of transfected ras. Similarly, SPP1 expression was strongly induced by ras in NIH 3T3 cells but was repressed by ras in LTA cells. Enzymogram assays for functional gelatinase activity showed an increase in 67-kd and 62-kd bands in NIH 3T3 cells in the presence of ras. LTA cells showed no gelatinolytic activity in the presence or absence of ras. Data from an in vitro assay for chemoinvasiveness showed a pattern as predicted from the expression of invasion-related genes; chemoinvasiveness in ras-transfected NIH 3T3 was greater than in LTA and ras-transfected LTA cells, which was greater than in NIH 3T3 cells. Differences in expression of the genes examined are believed to contribute to the ras responsiveness of NIH 3T3 cells and the ras resistance of LTA cells.

Animals↗

PubMed2005

Effect of normothermic liver ischemic preconditioning on the expression of apoptosis-regulating genes C-jun and Bcl-XL in rats.

AIM: To explore the expression of apoptosis-regulating genes C-jun and Bcl-XL after normothermic liver ischemic preconditioning and its protective effect on hepatocytes in the rat. METHODS: Wistar rats are randomly divided into sham operation group (S group, n = 10), ischemic reperfusion group (IR group, n = 10) and ischemic preconditioning group (IP group, n = 10). After dissection of the hepatoduodenal ligament in S group, and after 30-min reperfusion in IR group and in IP group, the samples of liver tissue were taken for studying the hepatocellular apoptosis, the expressions of C-jun mRNA, Bcl-XL mRNA and their proteins, and morphologic changes at 0, 3, 6, 20 h. Meanwhile the venous blood samples were drawn at 3, 6 and 20 h for testing ALT, AST and LDH. RESULTS: The levels of ALT, AST and LDH in IR group and IP group were significantly higher than those in S group. Hepatocellular apoptosis was significantly increased in both IR group and IP group, especially in IR group. Expressions of C-jun mRNA and protein were significantly increased in IR group compared with those in both IP group and S group, but no significant difference between IP group and S group (P>0.05). Expressions of Bcl-XL mRNA and protein in IR group and S group were not significant (P>0.05), but were significantly increased in IP group compared with those in both S group and IR group. Patch necrosis of hepatocytes because of severe injury could be seen in IR group microscopically, and the ultrastructural changes were irreversible. Meanwhile in IP group, no hepatocellular necrosis occurred, and the ultrastructural changes were reversible because of mild injury. CONCLUSION: (1) IP can protect the rat liver from normothermic IR injury by modulation of the expression of apoptosis-regulating genes C-jun and Bcl-XL; (2) IR injury may activate the apoptosis of hepatocytes by increasing the expression of apoptosis-inducing gene C-jun; (3) IP may prohibit the apoptosis of hepatocytes by increasing the expression of apoptosis-inhibitory gene Bcl-XL.

Animals↗

PubMed1996

Phosphorus intake regulates intestinal function and polyamine metabolism in uremia.

This study found that 5/6-nephrectomized uremic rats showed secondary hyperparathyroidism as reflected by an increase in their serum parathyroid hormone (PTH) level in association with a decrease in serum 1,25-dihydroxyvitamin D [1,25-(OH)2D]. These changes recovered partially upon phosphorus restriction. Calcium absorption and gene expression of calbindin-D9k were decreased in uremia and were also improved by phosphorus restriction. In uremia, intestinal spermidine/spermine N1-acetyltransferase activity was decreased, while ornithine decarboxylase (ODC) activity and its gene expression were potentiated. Enhancement of c-fos and c-jun gene expressions was also observed in uremia. These phenomena suggest that the intestinal villus may proliferate in uremia. Phosphorus restriction prevented increases in the expression of ODC, c-fos and c-jun observed in uremia. Since phosphorus restriction caused a rise in the serum 1,25-(OH)2D level, the role of 1,25-(OH)2D in uremia-induced intestinal dysfunction was examined. A single injection of 1,25-(OH)2D3 to uremic rats caused an increase in the steady-state calbindin-D9k mRNA level, and decreases in steady state c-fos and ODC mRNA levels, suggesting that the deficiency of 1,25-(OH)2D3 is responsible for intestinal dysfunction in uremia. In conclusion, altered polyamine metabolism caused by 1,25-(OH)2D deficiency is intimately involved in intestinal dysfunction and the development of the proliferative state of the intestinal villus in uremia.

Absorption↗

PubMed2004

Structural and functional analysis of the differential effects of c-Jun and v-Jun on prolactin gene expression.

The protooncogene c-Jun and its oncogenic isoform v-Jun are members of the activator protein 1 family of transcription factors that have been shown to have differential transcriptional effects that are both promoter specific and cell type specific. Previously, we have demonstrated that whereas c-Jun inhibits pituitary-specific rat prolactin (rPRL) promoter activity, expression of v-Jun stimulates the rPRL promoter in GH4 pituitary cells. In this report, we have conducted an extensive structure-function analysis of c-Jun vs. v-Jun to determine which regions of these proteins are responsible for their differential transcriptional effects in this pituitary model system. We show that isoform-specific responses are mediated by complex interactions between the delta-domain, serine 243, and the amino-terminal transcriptional activation domains. Thus, in contrast to previous reports, no single domain is responsible for the differential transcriptional activities of c-Jun and v-Jun. Mutation of c-Jun serine 243 to phenylalanine and replacement of the c-Jun amino terminus with the corresponding region from v-Jun, thereby removing the delta-domain, are necessary and sufficient to confer a functional switch from the c-Jun-inhibitory to the v-Jun-activating phenotype. Thus, we propose that isoform-specific subdomains in c-Jun and v-Jun dictate discrete interactions with distinct protein partners, which underlie the differential Jun-dependent transcriptional responses of the rPRL promoter.

Animals↗