Expression Of Multidrug Resistance Gene Research Articles

Alteration of Canalicular Transporters in a Mouse Model of Total Parenteral Nutrition

Parenteral nutrition-associated liver disease (PNALD) is a major problem with prolonged total parenteral nutrition (TPN) administration. Our laboratory previously demonstrated significant changes in the expression of multidrug resistance genes (MDRs) 1 and 2, hepatocyte transporters, in a TPN mouse model. The present study hypothesized that these changes would lead to functional changes in the liver, and would contribute to the development of liver dysfunction. Mice received either intravenous saline and standard chow or TPN with or without intravenous lipids. Functional assays were performed after 7 days of infusion. TPN with lipids led to a significant increase in serum bile acid levels, consistent with an early state of PNALD. Use of TPN without lipids prevented an elevation in bile acid levels. In both TPN groups, MDR2 expression was significantly (68%) lower than controls and bile phosphatidylcholine content, a functional measure of MDR2, was 40% less than controls. MDR1 expression in the TPN with lipid group was 31% higher than controls, whereas in the TPN without lipids mice there was no significant change. Hepatocyte extrusion of rhodamine dye, a measure of MDR1 function, declined only in the TPN with lipid group. Peroxisome proliferator-activated receptor-alpha expression decreased in both TPN groups. Fenofibrate given with TPN resulted in an increased expression of MDR1 and MDR2, and functionally increased hepatocyte rhodamine extrusion and presence of bile phosphatidylcholine in the TPN with lipid group. The study shows that TPN led to alterations in the function of MDR1- and MDR2-expressed proteins. The changes help in the understanding of the mechanisms leading to PNALD, and suggest that fibrate administration may palliate these changes.

Inhibition of HIF-1alpha activity by homeodomain-interacting protein kinase-2 correlates with sensitization of chemoresistant cells to undergo apoptosis.

BackgroundHomeodomain-interacting protein kinase-2 (HIPK2), a transcriptional co-repressor with apoptotic function, can affect hypoxia-inducible factor 1 (HIF-1) transcriptional activity, through downmodulation of its HIF-1α subunit, in normoxic condition. Under hypoxia, a condition often found in solid tumors, HIF-1α is activated to induce target genes involved in chemoresistance, inhibition of apoptosis and tumor progression. Here, we investigated whether the HIPK2 overexpression could downregulate HIF-1α expression and activity in tumor cells treated with hypoxia-mimicking condition, and evaluated whether HIPK2-dependent downregulation of HIF-1α could sensitize chemoresistant tumor cells to adriamycin (ADR)-induced apoptosis.MethodsTumor cell lines carrying wild-type p53, siRNA p53, or mutant p53 were overexpressed with HIPK2 (full length or catalytic inactive mutant) and treated with cobalt chloride (CoCl2) to mimic hypoxia, in the presence or absence of ADR treatment. HIF-1α expression was measured by semiquantitative reverse-transcriptase (RT)-PCR and Western immunoblotting and HIF-1 activity was evaluated by luciferase assay using reporter plasmid containing hypoxia response elements (HREs) upstream of luciferase gene. HIF-1 target genes, including multidrug resistance 1 (MDR1) and the antiapoptotic Bcl2 were determined by RT-PCR. Cell survival and apoptosis were measured by colony assay and cleavage of the caspase-3 substrate PARP, respectively.ResultsOverexpression of HIPK2 resulted in downmodulation of cobalt-stabilized HIF-1α protein and HIF-1α mRNA levels, with subsequent inhibition of HIF-1 transcriptional activity. MDR1 and Bcl-2 gene expression was downmodulated by HIPK2 overexpression in cobalt-treated cells. Inhibition of HIF-1 transcriptional activity was dependent on HIPK2 catalytic activity. HIPK2 overexpression did not induce per se apoptosis of cobalt-treated cells, on the contrary it sensitized cobalt-treated cells to ADR-induced apoptosis, regardless of their p53 status.ConclusionThe ability of HIPK2 to restore the apoptosis-inducing potential of chemotherapeutic drug in hypoxia-mimicking condition and therefore to sensitize chemoresistant tumor cells suggests that HIPK2 may induce fundamental alterations in cell signaling pathways, involving or not p53 function. Thus potential use of HIPK2 is promising for cancer treatment by potentiating cytotoxic therapies, regardless of p53 cell status.

PL-03 Harnessing multidrug resistance gene expression for effective antifungal strategies by a natural product berberine

PL-03 Harnessing multidrug resistance gene expression for effective antifungal strategies by a natural product berberine

Expression and clinical significance of multidrug resistance gene in epithelial ovarian cancer

Objective To study the expression of muhidrug resistance( MDR1 ) ,and clinical significance of MDR1 gone expression in EOC. Methods Reverse transcription polymerase chain reaction was used to determine the expression of MDR1 in 27 cases of epithelial ovarian cancer,38 cases of benign tumor and 20 cases of normal ovarian tissue. The expression rate of MDR1 and the clinical significance was explored. Results The expression rate of MDR1 gone in malignant,benign tumor and normal tissue of ovary was74.1%, 15.7 % and 0 % respectively. The levd of MDR1 gone expression in EOC was obviously higher than that in benign tumor(P<0.01 ). The non-respond-era to combination chemotherapy exhibited higher ratio of MDR1 expression than the respondera( P<0.05 ). Conclu-sion The expression of MDR1 is higher in EOC than that in normal ovary tissue and benign tumor. The expression of MDR1 is closely related to the tumor response to chemotherapy. Key words: Ovarian Cancer; Muhidmg rosistance-associated proteins

Pediatric glioblastoma cell line shows different patterns of expression of transmembrane ABC transporters after in vitro exposure to vinblastine

Resistance to drug is a major cause of treatment failure in pediatric brain cancer. The multidrug resistance (MDR) phenotype can be mediated by the superfamily of adenosine triphosphate-binding cassette (ABC) transporters. The dynamics of expression of the MDR genes after exposure to chemotherapy, especially the comparison between pediatric brain tumors of different histology, is poorly described. To compare the expression profiles of the multidrug resistance genes ABCB1, ABCC1, and ABCG2 in different neuroepithelial pediatric brain tumor cell lines prior and following short-term culture with vinblastine. Immortalized lineages from pilocytic astrocytoma (R286), anaplasic astrocytoma (UW467), glioblastoma (SF188), and medulloblastoma (UW3) were exposed to vinblastine sulphate at different schedules (10 and 60 nM for 24 and 72 h). Relative amounts of mRNA expression were analyzed by real-time quantitative polymerase chain reaction. Protein expression was assessed by immunohistochemistry for ABCB1, ABCC1, and ABCG2. mRNA expression of ABCB1 increased together with augmenting concentration and time of exposure to vinblastine for R286, UW467, and UW3 cell lines. Interestingly, ABCB1 levels of expression diminished in SF188. Following chemotherapy, mRNA expression of ABCC1 decreased in all cell lines other than glioblastoma. ABCG2 expression was influenced by vinblastine only for UW3. The mRNA levels showed consistent association to protein expression in the selected sets of cell lines analyzed. The pediatric glioblastoma cell line SF188 shows different pattern of expression of multidrug resistance genes when exposed to vinblastine. These preliminary findings may be useful in determining novel strategies of treatment for neuroepithelial pediatric brain tumors.

CD34 expression is associated with poor survival in pediatric T‐cell acute lymphoblastic leukemia

Children with T-lineage acute lymphoblastic leukemia (T-ALL) have an inferior outcome with combination chemotherapy compared to B-lineage ALL, and still about 30% of the patients relapse within the first 2 years following diagnosis. As CD34 has been related with poor outcome in ALL in general, we investigated the prognostic significance of the stem cell marker CD34, as well as the association of CD34 positivity with the expression of several multidrug resistance (MDR) genes. In this retrospective study, we investigated the prognostic significance of the expression of the early T-cell differentiation marker CD34 and the expression of MDR genes in relation to outcome in a cohort of 72 newly diagnosed pediatric T-ALL patients. CD34 expression was related to a poor 5-year disease-free-survival and a poor 5-year overall survival. Using the Cox proportional hazard model, CD34 expression predicted for increased risk for relapse and death. Expression of CD34 was associated with elevated MDR1 and MRP1 mRNA expression levels. For the entire T-ALL cohort, these expression levels of MDR1 or MRP1 did not independently predict for poor outcome. We conclude that CD34-positive T-ALL has a relatively poor survival that is not explained by the mRNA expression levels of MDR1, LRP, or MRP1.

The expression and significance of multi-drug resistance genes in breast cancer stem cells

Objective To approach the expressions of MDR1 and BCRP in breast cancer stem cells and differentiated cells.

Fractionated Irradiation Can Induce Functionally Relevant Multidrug Resistance Gene and Protein Expression in Human Tumor Cell Lines

The molecular basis of radiotherapy-related multidrug resistance (MDR) is still unclear. Here we report on a study investigating the effect of fractionated irradiation on expression of the MDR-associated proteins P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and lung resistance-related protein (LRP), the respective mRNAs, and the functional consequences. Cells of six colon and five breast cancer cell lines were irradiated with a total dose of 27 Gy, five fractions of 1.8 Gy per week. The mRNA expression was measured by quantitative RT-PCR, protein levels and drug sensitivity to cisplatin, doxorubicin and bendamustine were assessed by flow cytometry. Breast cancer cell lines showed enhancement of the mRNAs encoding for P-gp, MRP1 and LRP in comparison to nonirradiated cells. No up-regulation of the three mRNA species was observed in the colon cancer cell lines. After irradiation, three breast cancer cell lines showed an up-regulation of LRP, one line an up-regulation of MRP1, and four lines a small up-regulation of P-gp. In the colon cancer cell lines, radiation induced significant enhancement of all three proteins. In comparison to controls, the irradiated cells lines showed a significant resistance to cisplatin, doxorubicin and bendamustine. This study confirms the prior reports of enhancement of P-gp and MRP1 after irradiation, which is accompanied by a multidrug resistance phenomenon, but in addition proposes a novel mechanism in the appearance of MDR after radiation-induced enhancement of LRP.

Role of FoxO1 activation in MDR1 expression in adriamycin-resistant breast cancer cells

The development of multidrug resistance 1 (MDR1) can be mediated by a number of different mechanisms but elevated gene expression of MDR1 (P-glycoprotein) has often been a major cause of chemoresistance in many cancer cells. Therefore, the present study aimed to investigate the role of forkhead box-containing protein, O subfamily (FoxO), transcription factors in regulating the MDR1 gene expression. The proximal promoter region of the human MDR1 contained a putative FoxO-binding site, which partially overlapped with the enhancer/enhancer-binding protein beta-binding region. Gel shift and immunoblot analysis of subcellular fractions revealed that nuclear levels of FoxO1 and its DNA-binding activity were selectively enhanced in MCF-7/ADR cells, which was reversed by a FoxO1 antibody. Reporter gene assays showed that the transcription of MDR1 gene is stimulated by FoxO1 overexpression. Moreover, both MDR1 expression and doxorubicin resistance in MCF-7/ADR cells were reversed by FoxO1 small interfering RNA (siRNA). The MDR1 expression in MCF-7/ADR cells was also inhibited by insulin, a functional FoxO1 inactivator. In conclusion, FoxO1 is a novel transcriptional activator of MDR1 and is crucial for MDR1 induction in MCF-7/ADR cells.

Reversal effect of tyroservatide (YSV) tripeptide on multi-drug resistance in resistant human hepatocellular carcinoma cell line BEL-7402/5-FU

Tyroservatide (YSV) is an active, low-molecular-weight polypeptide that has been shown to have antitumor effects on human hepatocellular carcinoma BEL-7402 cells in vitro and in vivo. Multi-drug resistance (MDR) represents a major obstacle to the success of cancer chemotherapy. To enhance the chemosensitivity of tumor cells, attention has been focused on MDR modulators. In this study, we evaluated the reversal effect of YSV on MDR, and explored its mechanism of action in vitro. Administration of YSV reversed the multi-drug resistance of human hepatocellular carcinoma BEL-7402/5-FU cells significantly. The intracellular accumulation of doxorubicin and Rhodamine-123 (Rh123) were increased, which implied that the function of the P-glycoprotein (P-gp) efflux pump was inhibited by YSV. Moreover, the mRNA and protein expression of multi-drug resistance gene (MDR1) were also decreased by YSV. We observe that lung-resistance protein (LRP) and multi-drug resistance-associated protein (MRP1) each contribute to MDR in BEL-7402/5-FU cells as well. The mRNA and protein expression of LRP were decreased by YSV. No significant change was observed in mRNA expression of MRP1. However, we observe that the MRP1 protein level was reduced after treatment with YSV. These data demonstrate that YSV effectively reverses MDR in BEL-7402/5-FU cells, and that its mechanism of action is associated with the down-regulation of MDR1, MRP1 and LRP expression, as well as the inhibition of P-gp function.

Multi-drug resistance (MDR1/P-glycoprotein) gene expression in molecular breast cancer subtypes of African-American women

22038 Background: Molecular breast cancer subtypes respond differently to chemotherapy. Patients with the basal cell-like subtype despite initial chemosensitivity are associated with the worst distant-metastasis free survival. We sort to analyze the expression of the MDR1/P-glycoprotein gene among the molecular subtypes and its association with prognostic variables. Methods: A retrospective chart review for assessable immunohistochemical data for MDR1/P-glycoprotein, estrogen, progesterone and Her-2/neu on 232 patients diagnosed with breast cancer between 1998–2005. Subtypes analyzed were luminal A, luminal B, basal cell-like, and Her-2/neu. Results: Of the 232 patients 37 (15.9%) overexpressed while 195 (84.1%) underexpressed MDR1. As a function of the molecular subtypes no significant difference was noted in the expression of MDR1 (p=0.51). MDR1 overexpression was noted to be significantly associated with post-menopausal status (p=0.009), and low tumor grade (p=0.03). Patients with a low tumor grade were 3.1 times more likely to overexpress MDR1 (OR=3.1, 95% CI 1.0-11.5, p=0.03). MDR1 expression was not associated with lymph node metastasis, tumor size, or tumor stage. Treatment with chemotherapeutic drug was not associated with an increase in the proportion of tumors expressing MDR1 (OR=1.5, 95% CI 0.56-4.0, p=0.40). MDR1 expression showed no significant effect on overall survival (HR=1.4, 95% CI 0.51-4.00, p=0.49), or distant-metastasis free survival (HR=1.5, 95% CI 0.39-5.91, p=0.54). Conclusions: MDR1/P-glycoprotein expression does not differ among the molecular subtypes; however its expression is significantly associated with a low tumor grade and post-menopausal status, features associated with the luminal subtypes. No significant financial relationships to disclose.

Retroviral-mediated transfer and functional expression of multidrug resistance gene in human placenta mesenchymal stem cells

Most of gynecologic malignancies are sensitive to chemotherapy. Myelosuppression is the main dose-related toxicity of many chemotherapeutic drugs. The human multidrug resistance (mdr1) gene is well known for its ability to confer drug resistance. This study aimed to explore the feasibility of expression and resistance of mdr1 gene transduction into human placenta mesenchymal stem cells (P-MSCs) by retrovirus vector. Human P-MSCs were isolated from trypsin-digested term placentas, and their immunophenotypes and differentiation potential were evaluated. Human P-MSCs were transduced by reconstructed retroviral vector containing the mdr1 gene and green fluorescent protein (GFP) reporter gene. The integration and expression of the mdr1 gene were observed indirectly by the expression of GFP, and fluorescence-activated cell sorter was used to evaluate the functional activity of permeability glycoprotein (P-gp) encoded by the mdr1 gene. The stimulating test was made in vitro to show pleiotropic drug resistance of transfected cells. The isolated, cultured and expanded P-MSCs expressed stem cell markers such as CD29, CD44 and CD73, and showed osteogenic and adipogenic differentiation potentials under appropriate conditions. The expression of P-gp in the non-transfected P-MSCs cells was (0.4 +/- 0.1)%, but increased to (28.1 +/- 4.7)% after gene transfection (P < 0.01). And positive staining of P-gp located mainly at cell membrane and cytoplasm. Accumulation and extrusion assays showed that P-gp expressed by the transfected cells had pump-functional activity and could efflux daunomycin out of cells. The analysis of cell survival confirmed that transfected P-MSCs had a characteristic of multidrug resistance with a significant increase in the resistance to anticancer agents. Transfer and expression of human mdr1 gene mediated by retrovirus vector conferred P-MSCs drug resistance. It might provide a new alternative to chemoprotection strategies.

Expression of Multidrug Resistance Genes in Normal and Cancer Stem Cells

CD133 (stem marker) and drug resistant gene (mdr1 and bcl-2) expression were detected in human glioblastoma and normal brain tissues. Glioma tissues contained higher ratio of CD133+ cells compared to normal tissues (≈ 10 fold increase). The chemosensitivity assay showed that GOS-3 and NHA CD133+ possess greater resistance towards drugs compared to CD133- fractions. This study revealed for the first time that: a) serum deprivation enriched CD133 expression and demonstrated a direct co-expression between CD133 and drug resistant in GOS-3 cells and b) higher expression of CD133 and drug resistance were found in glioblastoma tissues in comparison to normal brain tissues.

Multidrug resistance 1 gene expression and AgNOR in childhood acute leukemias.

The multidrug resistance 1 (MDR1) gene product, P-glycoprotein (Pgp/p170) is a membrane protein, which acts as an ATP dependant efflux pump that expels a wide variety of organic compounds including chemotherapeutic agents from the cell. Pgp over expression has been demonstrated to be linked with poor treatment outcome and poor prognosis in a number of malignant tumors. AgNORs is a simple, reliable and inexpensive method of evaluating the proliferative activity of a tumor. We have studied MDR1 expression and AgNORS in 41 cases of acute leukemia in children. In this study, AgNOR counts in patients with acute lymphoblastic leukemia (ALL) L2 subtype (FAB classification) were significantly higher as compared to the ALL L1 subtype. Similarly, mean AgNOR count in the acute myeloid Leukemia (AML) M2 subtype was significantly higher as compared to the ALL L1 subtype. However, there was no correlation between AgNOR and treatment outcome or between AgNOR counts and MDR1 expression in any of the subtypes of acute leukemia included in this series. In AML, MDR1 gene expression was found to be related to reduced remission induction rates and hence poorer prognosis. In ALL, our study has shown no difference in remission induction between MDR1 positive and MDR1 negative cases. This would suggest that factors other than MDR1 may be of relevance in Pediatric ALL.

Poor Survival of CD34 Positive and CD13/33 Positive Patients in Pediatric T-Cell Acute Lymphoblastic Leukemia Is Not Explained by Expression of Multidrug Resistance Genes.

For childhood T-ALL, the significance of early differentiation markers CD34 and CD13/33 in relation to outcome is unclear. In this study of 72 pediatric T-ALL patients, CD34 and CD13/33 expression was related to a poor 5 yrs survival (p=0.0013 for CD34+ and p=0.035 for CD33/CD13+). Expression of CD34 was associated with elevated MDR1 (p=0.01) and MRP1 (p=0.019) levels and CD13/33+ expression with MRP1 levels (p=0.028). However, none of these MDR genes independently predicted for poor outcome. We conclude that T-ALL with CD34 and CD13/33 expression has a relatively poor survival that is not explained by expression of MDR genes.

Negative Transcriptional Regulation of Multidrug Resistance Gene Expression by an Hsp70 Protein

One of the most common origins of multidrug resistance occurs via the overproduction of ATP-binding cassette (ABC) transporter proteins. These ABC transporters then act as broad specificity drug pumps and efflux a wide range of toxic agents out of the cell. The yeast Saccharomyces cerevisiae exhibits multiple or pleiotropic drug resistance (Pdr) often through the over-production of a plasma membrane-localized ABC transporter protein called Pdr5p. Expression of the PDR5 gene is controlled by two zinc cluster-containing transcription factors called Pdr1p and Pdr3p. Cells that lack their mitochondrial genome (rho(0) cells) strongly induce PDR5 transcription in a Pdr3p-dependent fashion. To identify proteins associated with Pdr3p that might act to regulate this factor, a tandem affinity purification (TAP) moiety was fused to Pdr3p, and this recombinant protein was purified from yeast cells. The cytosolic Hsp70 chaperone Ssa1p co-purified with TAP-Pdr3p. Overexpression of Ssa1p repressed expression of PDR5 but had no effect on expression of other genes involved in the Pdr phenotype. This Ssa1p-mediated repression required the presence of Pdr3p and did not influence Pdr1p-dependent gene expression. Loss of the nucleotide exchange factor Fes1p mimicked Ssa1p-mediated repression of PDR5. Co-immunoprecipitation experiments indicated that Ssa1p was associated with Pdr3p but not Pdr1p in yeast cells. Finally, rho(0) cells had less Ssa1p bound to Pdr3p than rho(+) cells, consistent with Ssa1p-mediated repression of Pdr3p activity serving as a key regulatory step in control of multidrug resistance in yeast.

Expression of Multidrug Resistance 1 (MDR1), Multidrug Resistance-Related Protein 1 (MRP1), Lung Resistance Protein (LRP), and Breast Cancer Resistance Protein (BCRP) Genes and Clinical Outcome in Childhood Acute Lymphoblastic Leukemia

The aim of this prospective study was to analyze the expression of messenger RNA of genes, such as MDR1, MRP1, BCRP, and LRP, implicated in the mechanism of multidrug resistance (MDR) in relation to the response to induction chemotherapy and relapse and these genes' correlation with each other and with pretreatment laboratory and clinical characteristics. We prospectively studied 49 children (26 boys and 23 girls) with acute lymphoblastic leukemia (ALL) (median age, 5.5 years; range, 15 months to 12.5 years) who were treated with the BFM95 chemotherapy protocol. We used bone marrow mononuclear cells from 7 healthy children as controls. The expression of MDR genes and the beta-actin housekeeping gene was detected by the reverse transcription-polymerase chain reaction with the appropriate primers. The mean expression of each MDR gene was significantly higher in the patients than in the control group (P < .01). We found statistically significant correlations between MRP1 and LRP expression and between MRP1 or LRP expression and MDR1 expression (P < .05). High expression for the MDR1 gene was found in 18 patients (36.7%), and their prognoses were significantly worse than those with low expression (event-free survival, 55.56% versus 86.67%; P = .03, log-rank test). Expression of each of the MDR genes was independent of the initial white blood cell count, immunophenotype, National Cancer Institute risk classification, and prednisone response. Interestingly, MDR1 expression was significantly higher at relapse than at diagnosis for 4 sample pairs. Evaluation of MDR1 expression at diagnosis of childhood ALL may contribute to the early identification of patients at risk of treatment failure.

Cell type dependent regulation of multidrug resistance-1 gene expression by AML1-ETO

The AML1-ETO fusion protein is generated from the 8;21 chromosome translocation that is commonly identified in acute myeloid leukemia. AML1-ETO is a DNA binding transcription factor and has been demonstrated to play a critical role in promoting leukemogenesis. Therefore, it is important to define the molecular mechanism of AML1-ETO in the regulation of gene expression. Here, we report that the effect of AML1-ETO on the promoter of multidrug resistance-1 (MDR1) gene, a known AML1-ETO target, is highly cell type specific. Besides observing repression of the MDR1 promoter in C33A and CV-1 cells as reported previously, AML1-ETO strongly activated the promoter in K562 and B210 cells. More importantly, this activation required both the AML1 and ETO portions of the fusion protein, but did not depend on the AML1 binding site in MDR1 promoter. Furthermore, results from promoter deletion analysis and chromatin immunoprecipitation assays suggested that this activation effect was likely through the influence of the general transcription machinery rather than promoter-specific factors. Based on these data, we propose that AML1-ETO may have opposing effects on gene expression depending on the various conditions of the cellular environment.

A genome-wide steroid response study of the major human fungal pathogen Candida albicans

In the absence of steroid receptors and any known mechanism of gene regulation by steroid hormones in Candida albicans, we did a genome-wide analysis of C. albicans cells treated with progesterone using Eurogentec cDNA microarrays to find the complete repertoire of steroid responsive genes. Northern blotting analysis was employed to validate the genes that were differentially regulated by progesterone in the microarray experiments. A total of 99 genes were found to be significantly regulated by progesterone, among them 60 were up-regulated and 39 were down-regulated. It was observed that progesterone considerably enhanced the expression of multi-drug resistance (MDR) genes belonging to ATP Binding Cassette (CDR1 and CDR2) super-family of multidrug transporters, suggesting a possible relationship between steroid stress and MDR genes. Several genes associated with hyphal induction and the establishment of pathogenesis were also found up-regulated. In silico search for various transcription factor (TF) binding sites in the promoter of the affected genes revealed that EFG1, CPH1, NRG1, TUP1, MIG1 and AP-1 regulated genes are responsive to progesterone. The stress responsive elements (STRE; AG(4) or C(4)T) were also found in the promoters of several responsive genes. Our data sheds new light on the regulation of gene expression in C. albicans by human steroids, and its correlation with drug resistance, virulence, morphogenesis and general stress response. A comparison with drug induced stress response has also been discussed.

PO2-dependent Differential Regulation of Multidrug Resistance 1 Gene Expression by the c-Jun NH2-terminal Kinase Pathway

Hypoxia-induced multidrug resistance 1 (MDR1) gene expression is known to be mediated by c-Jun NH(2)-terminal kinase (JNK) activation. However, the molecular mechanisms underlying this action of JNK remain elusive. On the contrary, there has been increasing evidence for a negative correlation of JNK activity with MDR1 expression under normoxic conditions. Here, we present evidence that the JNK pathway represses MDR1 expression in normoxia and activates MDR1 expression in hypoxia. Our data show that JNK pathway-induced MDR1 repression in normoxia is mediated by increased c-Jun binding to activator protein 1 site, located in the MDR1 promoter, and requires the activity of histone deacetylase 5. In contrast, JNK pathway-induced MDR1 activation in hypoxia is independent of the activator protein 1 site. Rather, this action is dependent on increased hypoxia-inducible factor 1 (HIF1) binding to the hypoxia response element in the MDR1 promoter, which is promoted by the interaction of HIF1alpha with c-Jun in the nucleus and requires the activity of the p300/CBP (CREB-binding protein) coactivator.