Mdr1b facilitates p53-mediated cell death and p53 is required for Mdr1b upregulation in vivo

Lecureur, Valérie; Thottassery, Jaideep V.; Sun, Daxi; Schuetz, Erin G.; Lahti, Jill M.; Zambetti, Gerard P.; Schuetz, John D.

doi:10.1038/sj.onc.1204065

Cited by 18 publications

(14 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…and HIF1 (3,18). In addition, cross-coupled nuclear factor-B/p65 and c-Fos transcription factors are shown to bind to the CAAT box in the MDR1 promoter, to negatively regulate MDR1 expression (30), and p53 is shown to regulate MDR1 either positively or negatively (31,32). The data in the present study show that the JNK pathway-induced down-regulation of MDR1 in normoxia is mediated by increased c-Jun binding to the AP1 site in the MDR1 promoter, whereas the JNK pathway-induced up-regulation of MDR1 in hypoxia is mediated by increased HIF1 binding to the HRE in the MDR1 promoter.…”

Section: Discussionmentioning

confidence: 99%

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

Liu

Aneja

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

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 HIF1␣ with c-Jun in the nucleus and requires the activity of the p300/CBP (CREB-binding protein) coactivator.Tissue hypoxia, a decrease in local oxygen tension (PO 2 ), is a common feature of developing tumors. Tumor cells develop various adaptive programs in response to hypoxia, including up-regulation of specific genes that promote tumor survival and growth (1). The key factor that regulates cellular adaptation to low PO 2 is hypoxia-inducible factor 1 (HIF1), 2 a heterodimer comprising ␣-and ␤-subunits (2). Although HIF1␣ protein is stable only in hypoxia and rapidly degraded in normoxia, HIF1␤ protein level is not altered by PO 2 . Under hypoxic conditions, HIF1␣ translocates to the nucleus and dimerizes with HIF1␤ to form HIF1, which then binds to the hypoxia response elements (HREs) of target genes and activates their transcription (2). Multidrug resistance 1 (MDR1) gene, encoding the transmembrane drug transporter P-glycoprotein, is induced in response to hypoxia (3, 4), which may contribute to the observed chemotherapeutic resistance of cancer cells under hypoxic conditions (5). Hypoxia-induced MDR1 expression is mediated by the binding of HIF1 to the HRE located in the MDR1 promoter (3). In addition, activation of the c-Jun NH 2 -terminal kinase (JNK), a member of the mitogen-activated protein kinase family, has been implicated in hypoxia-induced MDR1 expression (6 -8). However, it remains to be elucidated how JNK activation contributes to MDR1 expression in hypoxia. On the other hand, there is a growing body of evidence supporting a negative correlation of JNK activity with MDR1 expression under normoxic conditions (9 -11). It is unclear at present whether the discrepancy between these studies results from the use of different cell lines or the variation in experimental protocols or whether it simply reflects different roles for JNK in regulating MDR1 gene expression under normoxic and hypoxic conditions.In this study, our data demonstrate for the first time that the JNK pathway plays PO 2 -dependent different roles in regulating...

show abstract

Section: Discussionmentioning

confidence: 99%

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

Liu

Aneja

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The reason and mechanism for the different alterations in the two Abcb1 isoforms remain unknown, although it has been proposed that alterations in Abcb1b mRNA levels may compensate for the changes of Abcb1a [26] . In addition to their common function as a drug efflux transporter, the Abcb1 isoforms appear to have their own specific function: Abcb1a was reported to regulate cell volume by influencing swelling activated chloride currents via a protein kinase C sensitive phosphorylation site on P-GP [27] , while Abcb1b has been shown to be involved in apoptosis [28] and cellular stress [29,30] . However, these views remain controversial [31,32] .…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific alterations in expression and function of P-glycoprotein in streptozotocin-induced diabetic rats

et al. 2011

View full text Add to dashboard Cite

Aim: To investigate the changes of expression and function of P-glycoprotein (P-GP) in cerebral cortex, hippocampus, liver, intestinal mucosa and kidney of streptozocin-induced diabetic rats. Methods: Diabetic rats were prepared via a single dose of streptozocin (65 mg/kg, ip). Abcb1/P-GP mRNA and protein expression levels in tissues were evaluated using quantitative real time polymerase chain reaction (QRT-PCR) analysis and Western blot, respectively. P-GP function was investigated via measuring tissue-to-plasma concentration ratios and body fluid excretion percentages of rhodamine 123. Results: In 5-and 8-week diabetic rats, Abcb1a mRNA levels were significantly decreased in cerebral cortices and intestinal mucosa, but dramatically increased in hippocampus and kidney. In liver, the level was increased in 5-week diabetic rats, and decreased in 8-week diabetic rats. Abcb1b mRNA levels were increased in cerebral cortex, hippocampus and kidney, but reduced in liver and intestinal mucosa in the diabetic rats. Western blot results were in accordance with the alterations of Abcb1a mRNA levels in most tissues examined. P-GP activity was markedly decreased in most tissues of diabetic rats, except kidney tissues. Conclusion: Alterations in the expression and function of Abcb1/P-GP under diabetic conditions are tissue specific, Abcb1 specific and diabetic duration-dependent.

show abstract

“…Western Immunoblot Analysis-Transfected cells were lysed in reporter lysis buffer as described above and previously (23). Equal amounts of protein (50 g) were separated on SDS-polyacrylamide gels, transferred to nitrocellulose membranes, and probed with a polyclonal anti-p53 antibody (Ab7).…”

Section: Methodsmentioning

confidence: 99%

“…3) was performed on total RNA by RNase protection using the RiboQuant multiprobe ribonuclease protease protection assay system (PharMingen, San Diego, CA) according to manufacturer instructions. The protected products were analyzed as described previously (23).…”

Section: Methodsmentioning

confidence: 99%

“…The nucleotide sequence of the MDR1 promoter from Ϫ99 to Ϫ48 with the relevant transcription factor binding sites and the mutations introduced are shown. A, mutations at the inverted CCAAT box were introduced into pMDR1202 to generate 1202-CAAT mt (23). The MT MDR1 promoter plasmids (1202-CAAT mt and pMDR107-ets mt ) and the wt plasmids (pMDR1202 and pMDR107) were transfected into cells (10 g), and the relative activation was determined as described above.…”

Section: Fig 4 Ets-1 Activates the Human Mdr1 Promotermentioning

confidence: 99%

See 1 more Smart Citation

Mutant p53 Cooperates with ETS and Selectively Up-regulates Human MDR1 Not MRP1

Sampath

Sun

Kidd

et al. 2001

Journal of Biological Chemistry

Self Cite

214

175

View full text Add to dashboard Cite

The most frequently expressed drug resistance genes, MDR1 and MRP1, occur in human tumors with mutant p53. However, it was unknown if mutant p53 transcriptionally regulated both MDR1 and MRP1. We demonstrated that mutant p53 did not activate either the MRP1 promoter or the endogenous gene. In contrast, mutant p53 strongly up-regulated the MDR1 promoter and expression of the endogenous MDR1 gene. Notably, cells that expressed either a transcriptionally inactive mutant p53 or the empty vector showed no endogenous MDR1 up-regulation. Transcriptional activation of the MDR1 promoter by mutant p53 required an Ets binding site, and mutant p53 and Ets-1 synergistically activated MDR1 transcription. Biochemical analysis revealed that Ets-1 interacted exclusively with mutant p53s in vivo but not with wild-type p53. These findings are the first to demonstrate the induction of endogenous MDR1 by mutant p53 and provide insight into the mechanism.The emergence of drug resistance poses a major obstacle to the success of cancer chemotherapy. Tumor cells acquire drug resistance via many routes including alterations in transport, drug targets, metabolism, and/or genes regulating cell survival. The most common alterations in drug transport are increased expression of MDR1 1 (the gene product is P-glycoprotein (1, 2)) and the multidrug resistance-associated protein (MRP1) (3, 4). Both are energy-dependent anticancer drug efflux pumps and play critical roles in the response to chemotherapeutic drugs (e.g. vinca alkaloids, taxanes, and epipodophyllotoxins). Further, both MDR1 and MRP1 are expressed in colon tumors that frequently express mutant (MT) forms of p53 (5, 6) and are intractable to chemotherapy. Notably, we have shown directly that MDR1 in colon tumors is normally repressed by wild-type (wt) p53 (7). In an analogous fashion Wang and Beck (9) as well as Sullivan et al. (8) have shown that wt p53 represses MRP1. Many clinical studies show that MT p53 expression is associated with increased MDR1 and/or MRP1 expression (5, 10, 11). These findings are fully consistent with a loss of p53 repression leading to MDR1 or MRP1 up-regulation. However, it is just as likely that these genes could be up-regulated by the "gain-offunction" activity of MT p53s (12-14).p53 deletion or mutation is one of the most frequent alterations in human malignancy and is clearly a critical step in the progression of colorectal cancer (15). Close to 90% of the p53 mutations in human tumors results in a disruption of the DNA binding domain. This not only disrupts transrepression and sequence-specific transactivation but also confers a gain-offunction activity that was first demonstrated for many MT p53s as acquiring the ability to induce tumors (13). This property was associated with the capability of these MT p53s to stimulate the expression of an alternate set of endogenous genes (13, 14, 16) that could potentially promote tumor progression and impair therapeutic response. However, although c-myc has unequivocally been demonstrated to be an endogenous t...

show abstract

Mdr1b facilitates p53-mediated cell death and p53 is required for Mdr1b upregulation in vivo

Cited by 18 publications

References 44 publications

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

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

Tissue-specific alterations in expression and function of P-glycoprotein in streptozotocin-induced diabetic rats

Mutant p53 Cooperates with ETS and Selectively Up-regulates Human MDR1 Not MRP1

Contact Info

Product

Resources

About