Molecular Cancer Therapeutics CTRC-AACR San Antonio Breast Cancer Symposium Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kuwano, M.
Right arrow Articles by Kohno, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kuwano, M.
Right arrow Articles by Kohno, K.
Related Collections
Right arrow Therapeutics and Targets
Right arrow Therapeutics and Targets: Drug Mechanisms and Resistance
Mol Cancer Ther. 2004;3:1485-1492
© 2004 American Association for Cancer Research

Minireview

The role of nuclear Y-box binding protein 1 as a global marker in drug resistance

Michihiko Kuwano1, Yoshinao Oda6, Hiroto Izumi4, Song-Ju Yang1, Takeshi Uchiumi7, Yukihide Iwamoto8, Masakazu Toi9, Teruhiko Fujii1,2, Hideaki Yamana1,2, Hisafumi Kinoshita1,2, Toshiharu Kamura1,3, Masazumi Tsuneyoshi6, Kosei Yasumoto5 and Kimitoshi Kohno4

1 Research Center for Innovative Cancer Therapy of the 21st Century COE Program for Medical Science, and Departments of 2 Surgery and 3 Gynecology Obstetrics, Kurume University, Fukuoka, Japan; Departments of 4 Molecular Biology and 5 Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan; Departments of 6 Anatomic Pathology, 7 Medical Biochemistry, and 8 Orthopedic Surgery, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan; 9 Breast Oncology, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan

Requests for reprints: Kimitoshi Kohno, Department of Molecular Biology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. Phone: 81-93-691-7423; Fax: 81-93-692-2766. E-mail: k-kohno{at}med.uoeh-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Transcriptional Regulation of...
 Clinical Implications of PGP...
 Clinical Implications of Nuclear...
 Conclusion
 References
 
Gene expression can be regulated by nuclear factors at the transcriptional level. Many such factors regulate MDR1 gene expression, but what are the sequence elements and transcription factors that control the basal and inducible expression of this gene? The general principles through which transcription factors participate in drug resistance are now beginning to be understood. Here, we review the factors involved in the transcriptional regulation of the MDR1 gene. In particular, we focus on the transcription factor Y-box binding protein 1 and discuss the possible links between Y-box binding protein 1 expression and drug resistance in cancer, which are mediated by the transmembrane P-glycoprotein or non–P-glycoprotein.


   Introduction
Top
 Abstract
 Introduction
Transcriptional Regulation of...
 Clinical Implications of PGP...
 Clinical Implications of Nuclear...
 Conclusion
 References
 
Drug export from cells is mediated through a group of proteins belonging to the ATP binding cassette family of transporters. The 170-kDa transmembrane protein P-glycoprotein (PGP), which is encoded by the multidrug resistance 1 (MDR1) gene, is a representative example of an ATP binding cassette transporter. PGP consists of two membrane-spanning domains and two nucleotide binding domains and has been reported to affect the pharmacokinetics of drugs by limiting the rate at which they are absorbed (1–5). Various molecules are targeted by drug treatments for cancer; however, PGP expression is responsible for resistance to the widest range of anticancer drugs (6, 7).

The expression of MDR1/PGP in human malignant cancers is expected to play a critical role in limiting their sensitivity to anticancer agents. Therefore, the determination of MDR1 gene expression levels, along with studies of the regulatory mechanisms of this gene, will be useful in developing tailor-made therapeutic strategies for cancer patients.

The partial sequence of the human MDR1 gene was first reported in the 1980s (8), and its complete sequence, including clustered CpG sites that are not associated with a TATA box, is now known (9). Within the MDR1 promoter sequence, a GC box forming a Sp1 site and an inverted CCAAT (ATTGG) site for Y-box binding protein 1 (YB-1) or nuclear factor Y (NF-Y) binding both play key roles in MDR1 gene expression (10).

MDR1 gene expression is often observed in recurrent cancers and appears after the chemotherapeutic treatment of various human malignancies. In cultured human cancer cells, the MDR1 promoter was activated by both PGP targeting drugs (vincristine and doxorubicin) and non-PGP-targeting drugs (5-fluorouracil and etoposide; ref. 11). In addition, treatment with retinoic acids and other differentiating agents resulted in enhanced expression of the MDR1 gene product PGP (12). Expression of the MDR1 gene was also up-regulated by heat shock, arsenate, and serum starvation in cultured human cancer cells (13–16). Consistent with these findings, MDR1 gene expression was markedly induced by anticancer agents (17); the gene promoter was also activated in response to both anticancer agents and UV light (18, 19). These results show that MDR1 gene expression is highly susceptible to various environmental stimuli (Table 1) and might therefore be stress responsive (11).


View this table:
[in this window]
[in a new window]
  		Table 1. Transcriptional regulation of the MDR1 gene in human cell lines

 
This review focuses on the molecular mechanism of the transcriptional regulation of human MDR1/PGP and the role of YB-1 expression in the acquisition of drug resistance.


   Transcriptional Regulation of the Human MDR1 Gene
Top
 Abstract
 Introduction
 Transcriptional Regulation of...
Clinical Implications of PGP...
 Clinical Implications of Nuclear...
 Conclusion
 References
 
Many studies have shown the involvement of various cis-acting elements in MDR1 gene expression, suggesting pleiotropic mechanisms (10). As shown in Table 1, several transcription factors are expected to play critical roles in the basal expression of the MDR1 promoter in addition to stimulus-induced activation.

Y-Box Binding Protein 1
Many reports on the factors associated with drug resistance have shown a plausible association of YB-1 with drug resistance both in cultured cancer cells and in numerous clinical human tumor samples.

YB-1 is a member of the cold shock domain (CSD) protein family, which is found in the cytoplasm and nucleus of mammalian cells. It has pleiotropic functions in the regulation of gene transcription and translation, DNA repair, drug resistance, and cellular responses to environmental stimuli (20–22). The structures of YB-1 and two other members of the CSD family, hdbpA (23) and Contrin/hdbpC (24), are presented in Fig. 1A. The YB-1 gene, which is located on chromosome 1p34 (25, 26), contains eight exons spanning 19 kb of genomic DNA (Fig. 1B). The 1.5-kb mRNA encodes a 43-kDa protein comprising three domains: a variable NH2-terminal tail domain (A/P domain), a highly conserved nucleic acid binding CSD, and a COOH-terminal tail domain (B/A repeat; refs. 27–29). The A/P domain (amino acids 1-51) seems to be involved in transcriptional regulation, whereas the CSD domain and part of the B/A repeat (amino acids 51-205) function in binding the Y-box (inverted CCAAT box) or double-stranded DNA. Most of the COOH-terminal region of the B/A repeat domain (amino acids 129-324) is thought to bind ssDNA or RNA, and part of this region (amino acids 129-205) is involved in dimerization.



View larger version (17K):
[in this window]
[in a new window]
  		Figure 1. A, protein structure and functional domains of hdbpB/YB-1, hdbpA, hdbpC, NF-YA, NF-YB, and NF-YC. A/P, alanine and proline domain, residues 1-82, 1-50, and 1-85 in hdbpA, hdbpB/YB-1, and Contrin/hdbpC, respectively. CSD, residues 83-161, 51-129, and 86-164. B/A repeat, basic and acidic amino acid, residues 162-372, 130-324, and 165-364. The CSD domains of the three genes are highly homologous. Of the three subunits of NF-Y, NF-YB and NF-YC contain histone folding motifs homologous to the yeast transcription factors HAP3 and HAP5, respectively. NF-YA contains a domain homologous to HAP2, which interacts with NF-YB and NF-YC, and the heterotrimer of NF-Y binds to DNA. Both NF-YA and NF-YC contain glutamine-rich domains and activate transcription. B, general structure of the genomic DNA, mRNA, and protein product of YB-1. The gene is mapped at chromosome 1p34 and has eight exons (E1, E2, E3, E4, E5, E6, E7, and E8). The YB-1 protein consists of 324 amino acids. B, basic amino acid clusters; A, acidic amino acid clusters.

 
We identified YB-1 as a transcription factor that binds to the inverted CCAAT box of the MDR1 promoter (30). Decreased expression of YB-1, resulting from the introduction of YB-1 antisense expression constructs into cancer cells, markedly reduced the activation of the MDR1 gene by DNA-damaging agents (31).

YB-1 is normally present in the cytoplasm, although it is translocated to the nucleus when cells are exposed to anticancer agents, hyperthermia, or UV light irradiation (19, 32, 33). YB-1 is often overexpressed in malignant cells and its expression is regulated by both the proto-oncogene product c-Myc and the tumor suppression gene product p73 (25, 34). The COOH-terminal tail domain seems to play a key role in the localization of YB-1 to either the cytoplasm or the nucleus (32). Studies have shown that cell cycle–specific nuclear translocation is mediated by cooperation of the CSD and COOH-terminal tail domain (35) and that the nuclear translocation of YB-1 requires wild-type p53 (36). The introduction of antisense RNA into human cancer cell lines,10 and the targeted disruption of one Y-box allele in chicken DT40 cells (37) both inhibited growth. By contrast, the targeted disruption of one allele of the YB-1 gene in mouse ES-1 cells had no effect on the growth rate (38).

Nuclear Factor Y
The CCAAT box is among the most ubiquitous DNA elements in both forward and reverse orientation. NF-Y is the major transcription factor recognizing the CCAAT box (39). This heteromeric protein is composed of three subunits, NF-YA, NF-YB, and NF-YC, all of which are necessary for DNA binding (Fig. 1A). Mutation and/or deletion of the CCAAT box have been shown to result in a significant loss of MDR1 promoter activity (40). It has been reported that both the inverted CCAAT box and the GC box are required for activation of the MDR1 promoter by UV light, and NF-Y, not YB-1, is thought to be the factor regulating the MDR1 gene (41). However, these findings are not consistent with the results discussed above. The YB-1 protein is abundant and localized in the cytoplasm; however, when the effect of YB-1 overexpression on MDR1 promoter activity was evaluated in human cancer KB cells, it was unclear whether the nuclear YB-1 content was increased. As YB-1 is known to repress translation, increased levels of cytoplasmic YB-1 might inhibit the translation of luciferase mRNA. Further studies are required to resolve this issue. Treatment with a histone deacetylase inhibitor (trichostatin) induced a marked increase in the amount of MDR1 mRNA, although this drug-induced increase was inhibited in dominant-negative NF-Y mutants (42). NF-Y therefore seems to regulate MDR1 gene expression through an interaction with p300/CBP-associated factor, which shows histone acetylation activity. NF-Y might also be responsible for the sodium butyrate–induced MDR1 gene up-regulation in colon cancer cells (43). This transcription factor therefore plays a pivotal role in MDR1 gene expression. Recently, the antitumor agent HMN-176, which interacts with NF-YB, has been shown to inhibit MDR1 gene expression and to restore chemosensitivity to MDR cells (44).

Sp1 and Early Growth Response Element 1
The introduction of mutations in the GC-rich region –59 to –45 (G region) of the MDR1 promoter markedly decreased its activity as a result of the transcription factor Sp1 (40, 45). Sp1 was first cloned and identified as a transcription factor specifically bound to the GC box of the SV40 promoter. A GC box is found in the promoter region of many eukaryotic genes. The Sp1 family is involved in various cellular functions including proliferation, apoptosis, differentiation, and neoplastic changes. As the early growth response element 1 (EGR1) binding motif partially overlaps with the Sp1 binding sites, it is conceivable that they mutually influence MDR1 gene expression in a competitive manner (45). Treatment with phorbol ester induced the expression of both EGR1 and MDR1 genes in human leukemia cells (46). However, the expression of EGR1 alone did not enhance MDR1 promoter activity. Coexpression of the oncosuppressor gene WT1 resulted in the inhibition of MDR1 promoter activation by EGR1 or phorbol ester (47). Therefore, the direct binding of WT1 to the GC box might compete with Sp1 to down-regulate the MDR1 gene. These findings suggest that interactions between EGR1 and WT1 might play a key role in MDR1 promoter activation.

p53
Mutant p53 has been shown to enhance MDR1 promoter activity in mouse cells; this was reversed by wild-type p53 (14, 48). By contrast, stimulation of the MDR1 promoter by wild-type, but not mutant, p53 was shown in several human p53-null cancer cell lines. The MDR1 promoter region –39 to +53 is responsible for this p53-mediated activation (49), whereas the region –189 to +133 is thought to be responsible for negative regulation by wild-type p53 (50). In addition, p53 has been reported recently to bind directly to a novel binding element (–72 to –40) within the MDR1 core promoter and to repress its promoter activity (51).

Nuclear Factor-Interleukin-6
The treatment of human monocytic cells with phorbol ester enhanced MDR1 promoter activity through interaction with nuclear factor-interleukin-6, which is a CCAAT/enhancer binding protein family member. This study also revealed that the mitogen-activated protein kinase pathway activates nuclear factor-interleukin-6 (52). In addition, CCAAT/enhancer binding protein ß has been shown recently to transactivate the MDR1 promoter by interaction with the Y-box (53).

Heat Shock Factor
MDR1 promoter activation in response to arsenate or heat shock seems to be mediated through a heat shock element in the –178 to –165 region. An additional region at –136 to –76 has also been proposed as a critical heat shock element for the heat shock response (15, 54), although no direct binding of heat shock factor to this region has been shown. Recently, Vilaboa et al. (55) reported that infection with adenovirus carrying heat shock transcription factor 1 cDNA increased the levels of MDR1 mRNA and PGP.

Transcription Factor 4/ß-Catenin
Transcriptional profiles produced using cDNA microarrays in human colon cancer cell lines identified the MDR1 gene as the target of transcription factor 4/ß-catenin. Seven transcription factor 4/ß-catenin binding sites were in the promoter region between –2,030 and +31 (56).

Nuclear Factor-{kappa}B
The hepatocarcinogen 2-acetylaminofluorene was shown to activate the MDR1 gene in human hepatoma cells and the induction of MDR1 by 2-acetylaminofluorene was mediated by a nuclear factor-{kappa}B binding site located around –6 kb (57). Another group showed that the inhibition of nuclear factor-{kappa}B reduced levels of MDR1 mRNA and PGP expression and that nuclear factor-{kappa}B transactivated the MDR1 promoter in human colon cancer HCT15 cells (58). This study identified a nuclear factor-{kappa}B binding site in the first intron.

MDR1 Promoter-Enhancing Factor 1/RNA Helicase A
MDR1 promoter-enhancing factor 1 has been shown to bind to the CCAAT sequence causing up-regulation of the MDR1 gene (59). RNA helicase A has also been reported to bind to the CCAAT box as a member of the MDR1 promoter-enhancing factor 1 complex (60). Overexpression of RNA helicase A enhanced the expression of both the MDR1 promoter-reporter construct and endogenous PGP.


   Clinical Implications of PGP Expression and Nuclear Translocation of YB-1
Top
 Abstract
 Introduction
 Transcriptional Regulation of...
 Clinical Implications of PGP...
Clinical Implications of Nuclear...
 Conclusion
 References
 
PGP triggers resistance to a wide range of anticancer agents including Vinca alkaloids, anthracyclines, epipodophyllotoxins, and taxols (7). In addition, YB-1 plays a role in limiting the drug sensitivity of cancer cells by increasing the expression of PGP and other proteins. Immunohistochemical studies of YB-1 expression in the nuclei of untreated primary breast cancers showed an almost complete association between nuclear YB-1 and PGP expression in 9 of 27 cases (Table 2; ref. 61). Studies of clinical specimens have also shown an association between YB-1 and PGP in osteosarcoma (62), synovial sarcoma (63), breast cancer (64, 65), ovarian cancer (66–68), and prostate cancer (Table 2; ref. 69). Figure 2 shows examples of the presence and absence of YB-1 and PGP in clinical samples of osteosarcoma and synovial sarcoma based on the results of immunohistochemical analyses with anti-YB-1 and anti-PGP antibodies.


View this table:
[in this window]
[in a new window]
  		Table 2. The association of nuclear expression of YB-1 with PGP-mediated and/or non-PGP-mediated drug resistance in human malignancies

 


View larger version (149K):
[in this window]
[in a new window]
  		Figure 2. Immunohistochemical detection of nuclear and cytoplasmic YB-1 in osteosarcoma and synovial sarcoma. Antibodies were used against YB-1 (A, B, D, and E) or PGP (C and F). Osteosarcoma is shown with cytoplasmic YB-1 expression (A), nuclear YB-1 expression (B), and PGP expression (C). Synovial sarcoma is shown with cytoplasmic YB-1 expression (D), nuclear YB-1 expression (E), and PGP expression (F). The patient in D showed no evidence of disease 131 months after surgery. The patient in F died of lung metastasis 8 months after the initial surgery.

 
There was a significant correlation between the nuclear expression of YB-1 and the presence of PGP in 69 cases of osteosarcomas (62). A recent study confirmed that YB-1 expression was specifically associated with the overexpression of PGP rather than with three other ATP binding cassette transporters: MRP1, MRP2, and MRP3 (63). By contrast, no association was observed between YB-1 and PGP expression in colon cancers (70). It remains unclear whether YB-1 is directly involved in the transcriptional regulation of PGP in human malignancies. Nevertheless, measurements of the expression of YB-1 and PGP could suggest treatment modalities for individual cancer patients. Recently, we showed that coexpression of YB-1 and PGP correlated with poor prognosis in epithelial ovarian cancer (67). The expression of MDR1 is augmented in cancerous areas in breast cancer and other tumors, resulting in drug resistance. Furthermore, the presence of YB-1 in the nuclei of cancer cells is closely associated with the clinical outcome. YB-1 could therefore be a useful indicator of malignancy as well as a promising target for cancer therapy. We recommend the use of non-PGP-targeting drugs against malignant tumors with nuclear YB-1 expression.


   Clinical Implications of Nuclear Localization of YB-1: Drug Resistance to non-PGP-Targeting Drugs
Top
 Abstract
 Introduction
 Transcriptional Regulation of...
 Clinical Implications of PGP...
 Clinical Implications of Nuclear...
Conclusion
 References
 
As described above, YB-1 is translocated to the nucleus in response to various environmental stresses including UV light, anticancer agents, heat, and infection in cultures of cancer cells (21). YB-1 was shown to be overexpressed in cisplatin-resistant cell lines, and antisense YB-1 RNA triggered the augmentation of sensitivity to cisplatin, mitomycin C, UV light, and hydrogen peroxide (30, 38). YB-1 associates with p53 (71) and proliferating cell nuclear antigen (72), both of which modulate DNA repair, cell cycle, transcription, and drug sensitivity. Moreover, wild-type p53 is required for the nuclear translocation of YB-1, which in turn inhibits p53-induced cell death (36). However, it remains unclear how reduced YB-1 expression increases resistance to non-PGP-targeting DNA-damaging agents such as cisplatin and mitomycin C. Potential mechanisms might include a reduction in the YB-1 interaction with proliferating cell nuclear antigen, which is necessary for nucleotide excision repair, or in the interaction with p53. However, pleiotropic drug resistance to DNA-interacting drugs (e.g., aphidicolin, hydroxyurea, cytarabine, etoposide, doxorubicin, and mafosfamide) is associated with the increased expression of YB-1 and 19 other genes that are involved in DNA replication, repair, and stress responses (73).

Nuclear expression of YB-1 was reported to be a prognostic factor in ovarian serous adenocarcinoma (66). It was also associated with cisplatin resistance in ovarian cancer cell lines, and expression levels were increased at some sites of ovarian cancer recurrence (68). This pattern was seen in 7 of 21 serous adenocarcinomas, 2 of 7 clear cell adenocarcinomas, and 1 of 4 mucinous adenocarcinomas (Table 2). There was also a positive correlation between the nuclear expression of YB-1 and poor prognosis in synovial sarcoma (63).

Analysis of the clinical relevance of YB-1 expression in the cytoplasm or nucleus in 83 cases of breast cancer, after a median follow-up of 61 months, revealed that the 5-year relapse rate was 66% in patients with high YB-1 expression who received postoperative chemotherapy (65). By contrast, none of the patients with low YB-1 expression experienced relapse. Taken together, these findings indicate that the overexpression and nuclear expression of YB-1 have a predictive value in some human malignancies, both with and without postoperative chemotherapy.

An investigation of 588 genes associated with mouse lung tumor progression revealed that 19 were differentially expressed between lung adenoma and adenocarcinoma; YB-1 was one of these candidate lung tumor progression genes (74). Overexpression of YB-1 was observed in >90% of anaplastic thyroid carcinomas, whereas it was absent in normal follicles and other pathologic tumor types. These findings suggested the involvement of YB-1 in the anaplastic transformation of thyroid carcinoma (75). YB-1 expression induced a strong cellular resistance to malignant transformation through the phosphatidylinositol 3-kinase pathway possibly through the inhibition of protein synthesis that is required for the phosphatidylinositol 3-kinase– or Akt-induced oncogenic transformation (76).


   Conclusion
Top
 Abstract
 Introduction
 Transcriptional Regulation of...
 Clinical Implications of PGP...
 Clinical Implications of Nuclear...
 Conclusion
References
 
The ancestral protein YB-1 modulates cell growth, apoptosis, drug resistance, DNA repair, transcription, and translation as a pleiotropic regulator. YB-1 overexpression or nuclear YB-1 expression might play a key role not only in the acquirement of PGP-mediated drug resistance but also in sensitivity to non-PGP-targeting chemotherapeutic agents. YB-1 in the nucleus modulates drug resistance to PGP-targeting and non-PGP-targeting drugs in cancer cells that are exposed to anticancer and other cytotoxic DNA-damaging agents (Fig. 3). In one response pathway to environmental stimuli, YB-1 is translocated to the nucleus and up-regulates MDR1 gene expression through binding to the Y-box on the promoter. Alternatively, YB-1 might operate its DNA repair pathway through interactions with p53 (71), proliferating cell nuclear antigen (72), and other molecules (77) when DNA is damaged (Fig. 3). Further research is needed to fully understand the role of YB-1 in cancer and drug resistance.



View larger version (19K):
[in this window]
[in a new window]
  		Figure 3. Schematic summary of MDR mediated by PGP or non-PGP. YB-1 is normally present in the cytoplasm but is translocated to the nucleus by treatment with anticancer agents, hyperthermia, or UV light irradiation. YB-1 in the nucleus functions as a transcription factor, which can bind to the Y-box and transactivate promoters, such as the MDR1 gene or repair genes. By contrast, YB-1 can bind directly to cisplatin-modified DNA and interact with repair proteins including NTH1 (Exo III) and proliferating cell nuclear antigen (PCNA). These functions might be advantageous for the acquisition of drug resistance.

 

   Acknowledgments
 
We thank our colleagues for invaluable help in completing the studies presented in this article.


   Footnotes
 
Grant support: Ministry of Education, Science, Technology, Sports and Culture of Japan and Ministry of Health and Welfare of Japan.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

10 K. Kohno and M. Kuwano, unpublished data. Back

Received 5/21/04; revised 8/11/04; accepted 8/27/04.


   References
Top
 Abstract
 Introduction
 Transcriptional Regulation of...
 Clinical Implications of PGP...
 Clinical Implications of Nuclear...
 Conclusion
 References
 

  1. Schinkel AH, Mayer U, Wagenaar E, et al. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci U S A 1997;15:4028–33.
  2. Schinkel AH. Pharmacological insights from P-glycoprotein knockout mice. Int J Clin Pharmacol Ther 1998;36:9–13.[Medline]
  3. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 1999;39:361–98.[CrossRef][Medline]
  4. Watkins PB. The barrier function of CYP3A4 and P-glycoprotein in the small bowel. Adv Drug Deliv Rev 1997;15:161–70.
  5. Fromm MF. The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans. Adv Drug Deliv Rev 2002;18:1295–310.
  6. Scherf U, Ross DT, Waltham M, et al. A gene expression database for the molecular pharmacology of cancer. Nat Genet 2000;24:236–44.[CrossRef][Medline]
  7. Alvarez M, Paull K, Monks A, et al. Generation of a drug resistance profile by quantitation of mdr-1/P-glycoprotein in the cell lines of the National Cancer Institute Anticancer Drug Screen. J Clin Invest 1995;95:2205–14.
  8. Ueda K, Clark DP, Chen CJ, Roninson IB, Gottesman MM, Pastan I. The human multidrug resistance (MDR1) gene. cDNA cloning and transcription initiation. J Biol Chem 1987;262:505–8.[Abstract/Free Full Text]
  9. Kohno K, Sato S, Uchiumi T, Takano H, Kato S, Kuwano M. Tissue-specific enhancer of the human multidrug-resistance (MDR1) gene. J Biol Chem 1990;15:19690–6.
  10. Labialle S, Gayet L, Marthinet E, Rigal D, Baggetto LG. Transcriptional regulators of the human multidrug resistance 1 gene: recent views. Biochem Pharmacol 2002;64:943–8.[CrossRef][Medline]
  11. Kohno K, Sato S, Takano H, Matsuo K, Kuwano M. The direct activation of human multidrug resistance gene (MDR1) by anticancer agents. Biochem Biophys Res Commun 1989;165:1415–21.[CrossRef][Medline]
  12. Bates SE, Mickley LA, Chen YN, et al. Expression of a drug resistance gene in human neuroblastoma cell lines: modulation by retinoic acid-induced differentiation. Mol Cell Biol 1989;9:4337–44.[Abstract/Free Full Text]
  13. Chin KV, Tanaka S, Darlington G, Pastan I, Gottesman MM. Heat shock and arsenite increase expression of the multidrug resistance (MDR1) gene in human renal carcinoma cells. J Biol Chem 1990;265:221–6.[Abstract/Free Full Text]
  14. Chin KV, Ueda K, Pastan I, Gottesman MM. Modulation of activity of the promoter of the human MDR1 gene by Ras and p53. Science 1992;255:459–62.[Abstract/Free Full Text]
  15. Miyazaki M, Kohno K, Uchiumi T, et al. Activation of human multidrug resistance-1 gene promoter in response to heat shock stress. Biochem Biophys Res Commun 1992;187:677–84.[CrossRef][Medline]
  16. Tanimura H, Kohno K, Sato S, et al. The human multidrug resistance 1 promoter has an element that responds to serum starvation. Biochem Biophys Res Commun 1992;183:917–24.[CrossRef][Medline]
  17. Chaudhary PM, Roninson IB. Induction of multidrug resistance in human cells by transient exposure to different chemotherapeutic drugs. J Natl Cancer Inst 1993;85:632–9.[Abstract/Free Full Text]
  18. Asakuno K, Kohno K, Uchiumi T, et al. Involvement of a DNA binding protein, MDR-NF1/YB-1, in human MDR1 gene expression by actinomycin D. Biochem Biophys Res Commun 1994;199:1428–35.[CrossRef][Medline]
  19. Uchiumi T, Kohno K, Tanimura H, et al. Enhanced expression of the human multidrug resistance 1 gene in response to UV light irradiation. Cell Growth Differ 1993;4:147–57.[Abstract]
  20. Izumi H, Imamura T, Nagatani G, et al. Y box-binding protein-1 binds preferentially to single-stranded nucleic acids and exhibits 3'->5' exonuclease activity. Nucleic Acids Res 2001;29:1200–7.[Abstract/Free Full Text]
  21. Kohno K, Izumi H, Uchiumi T, Ashizuka M, Kuwano M. The pleiotropic functions of the Y-box-binding protein, YB-1. Bioessays 2003;25:691–8.[CrossRef][Medline]
  22. Kuwano M, Uchiumi T, Hayakawa H, et al. The basic and clinical implications of ABC transporters, Y-box-binding protein-1 (YB-1) and angiogenesis-related factors in human malignancies. Cancer Sci 2003;94:9–14.[Medline]
  23. Kudo S, Mattei MG, Fukuda M. Characterization of the gene for dbpA, a family member of the nucleic-acid-binding proteins containing a cold-shock domain. Eur J Biochem 1995;231:72–82.[Medline]
  24. Tekur S, Pawlak A, Guellaen G, Hecht NB. Contrin, the human homologue of a germ-cell Y-box-binding protein: cloning, expression, and chromosomal localization. J Androl 1999;20:135–44.[Abstract/Free Full Text]
  25. Makino Y, Ohga T, Toh S, et al. Structural and functional analysis of the human Y-box binding protein (YB-1) gene promoter. Nucleic Acids Res 1996;24:1873–8.[Abstract/Free Full Text]
  26. Toh S, Nakamura T, Ohga T, et al. Genomic organization of the human Y-box protein (YB-1) gene. Gene 1998;206:93–7.[CrossRef][Medline]
  27. Wolffe AP. Structural and functional properties of the evolutionarily ancient Y-box family of nucleic acid binding proteins. Bioessays 1994;16:245–51.[CrossRef][Medline]
  28. Ladomery M, Sommerville J. A role for Y-box proteins in cell proliferation. Bioessays 1995;17:9–11.[CrossRef][Medline]
  29. Graumann PL, Marahiel MA. A superfamily of proteins that contain the cold-shock domain. Trends Biochem Sci 1998;23:286–90.[CrossRef][Medline]
  30. Ohga T, Koike K, Ono M, et al. Role of the human Y box-binding protein YB-1 in cellular sensitivity to the DNA-damaging agents cisplatin, mitomycin C, and ultraviolet light. Cancer Res 1996;56:4224–8.[Abstract/Free Full Text]
  31. Ohga T, Uchiumi T, Makino Y, et al. Direct involvement of the Y-box binding protein YB-1 in genotoxic stress-induced activation of the human multidrug resistance 1 gene. J Biol Chem 1998;273:5997–6000.[Abstract/Free Full Text]
  32. Koike K, Uchiumi T, Ohga T, et al. Nuclear translocation of the Y-box binding protein by ultraviolet irradiation. FEBS Lett 1997;417:390–4.[CrossRef][Medline]
  33. Stein U, Jurchott K, Walther W, Bergmann S, Schlag PM, Royer HD. Hyperthermia-induced nuclear translocation of transcription factor YB-1 leads to enhanced expression of multidrug resistance-related ABC transporters. J Biol Chem 2001;276:28562–9.[Abstract/Free Full Text]
  34. Uramoto H, Izumi H, Ise T, et al. p73 Interacts with c-Myc to regulate Y-box-binding protein-1 expression. J Biol Chem 2002;277:31694–702.[Abstract/Free Full Text]
  35. Jurchott K, Bergmann S, Stein U, et al. YB-1 as a cell cycle-regulated transcription factor facilitating cyclin A and cyclin B1 gene expression. J Biol Chem 2003;278:27988–96.[Abstract/Free Full Text]
  36. Zhang YF, Homer C, Edwards SJ, et al. Nuclear localization of Y-box factor YB-1 requires wild-type p53. Oncogene 2003;22:2782–94.[CrossRef][Medline]
  37. Swamynathan SK, Varma BR, Weber KT, Guntaka RV. Targeted disruption of one allele of the Y-box protein gene, Chk-YB-1b, in DT40 cells results in major defects in cell cycle. Biochem Biophys Res Commun 2002;296:451–7.[CrossRef][Medline]
  38. Shibahara K, Uchiumi T, Fukuda T, et al. Targeted disruption of one allele of Y-box binding protein-1 (YB-1) gene in mouse embryonic stem cells and increased sensitivity to cisplatin and mitomycin C. Cancer Sci 2004;95:348–53.[Medline]
  39. Mantovani R. The molecular biology of the CCAAT-binding factor NF-Y. Gene 1999;239:15–27.[CrossRef][Medline]
  40. Sundseth R, MacDonald G, Ting J, King AC. DNA elements recognizing NF-Y and Sp1 regulate the human multidrug-resistance gene promoter. Mol Pharmacol 1997;51:963–71.[Abstract/Free Full Text]
  41. Hu Z, Jin S, Scotto KW. Transcriptional activation of the MDR1 gene by UV irradiation. Role of NF-Y and Sp1. J Biol Chem 2000;275:2979–85.[Abstract/Free Full Text]
  42. Jin S, Scotto KW. Transcriptional regulation of the MDR1 gene by histone acetyltransferase and deacetylase is mediated by NF-Y. Mol Cell Biol 1998;18:4377–84.[Abstract/Free Full Text]
  43. Morrow CS, Nakagawa M, Goldsmith ME, Madden MJ, Cowan KH. Reversible transcriptional activation of mdr1 by sodium butyrate treatment of human colon cancer cells. J Biol Chem 1994;269:10739–46.[Abstract/Free Full Text]
  44. Tanaka H, Ohshima N, Ikenoya M, Komori K, Katoh F, Hidaka H. HMN-176, an active metabolite of the synthetic antitumor agent HMN-214, restores chemosensitivity to multidrug-resistant cells by targeting the transcription factor NF-Y. Cancer Res 2003;63:6942–7.[Abstract/Free Full Text]
  45. Cornwell MM, Smith DE. Sp1 activates the MDR1 promoter through one of two distinct G-rich regions that modulate promoter activity. J Biol Chem 1993;268:19505–11.[Abstract/Free Full Text]
  46. McCoy C, Smith DE, Cornwell MM. 12-O-tetradecanoylphorbol-13-acetate activation of the MDR1 promoter is mediated by EGR1. Mol Cell Biol 1995;15:6100–8.[Abstract]
  47. Madden SL, Cook DM, Morris JF, Gashler A, Sukhatme VP, Rauscher FJ III. Transcriptional repression mediated by the WT1 Wilms tumor gene product. Science 1991;253:1550–3.[Abstract/Free Full Text]
  48. Thottassery JV, Zambetti GP, Arimori K, Schuetz EG, Schuetz JD. p53-dependent regulation of MDR1 gene expression causes selective resistance to chemotherapeutic agents. Proc Natl Acad Sci U S A 1997;94:11037–42.[Abstract/Free Full Text]
  49. Goldsmith ME, Gudas JM, Schneider E, Cowan KH. Wild type p53 stimulates expression from the human multidrug resistance promoter in a p53-negative cell line. J Biol Chem 1995;270:1894–8.[Abstract/Free Full Text]
  50. Strauss BE, Haas M. The region 3' to the major transcriptional start site of the MDR1 downstream promoter mediates activation by a subset of mutant P53 proteins. Biochem Biophys Res Commun 1995;217:333–40.[CrossRef][Medline]
  51. Johnson RA, Ince TA, Scotto KW. Transcriptional repression by p53 through direct binding to a novel DNA element. J Biol Chem 2001;276:27716–20.[Abstract/Free Full Text]
  52. Combates NJ, Kwon PO, Rzepka RW, Cohen D. Involvement of the transcription factor NF-IL6 in phorbol ester induction of P-glycoprotein in U937 cells. Cell Growth Differ 1997;8:213–9.[Abstract]
  53. Chen GK, Sale S, Tan T, Ermoian RP, Sikic, BI. CCAAT/enhancer-binding protein ß (nuclear factor for interleukin 6) transactivates the human MDR1 gene by interaction with an inverted CCAAT box in human cancer cells. Mol Pharmacol 2004;65:906–16.[Abstract/Free Full Text]
  54. Kioka N, Yamano Y, Komano T, Ueda K. Heat-shock responsive elements in the induction of the multidrug resistance gene (MDR1). FEBS Lett 1992;301:37–40.[CrossRef][Medline]
  55. Vilaboa NE, Galan A, Troyano A, de Blas E, Aller P. Regulation of multidrug resistance 1 (MDR1)/P-glycoprotein gene expression and activity by heat-shock transcription factor 1 (HSF1). J Biol Chem 2000;275:24970–6.[Abstract/Free Full Text]
  56. Yamada T, Takaoka AS, Naishiro Y, et al. Transactivation of the multidrug resistance 1 gene by T-cell factor 4/ß-catenin complex in early colorectal carcinogenesis. Cancer Res 2000;60:4761–6.[Abstract/Free Full Text]
  57. Kuo MT, Liu Z, Wei Y, et al. Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-{kappa}B signaling. Oncogene 2002;21:1945–54.[CrossRef][Medline]
  58. Bentires-Alj M, Barbu V, Fillet M, et al. NF-{kappa}B transcription factor induces drug resistance through MDR1 expression in cancer cells. Oncogene 2003;22:90–7.[CrossRef][Medline]
  59. Ogretmen B, Safa AR. Identification and characterization of the MDR1 promoter-enhancing factor 1 (MEF1) in the multidrug resistant HL60/VCR human acute myeloid leukemia cell line. Biochemistry 2000;39:194–204.[CrossRef][Medline]
  60. Zhong X, Safa AR. RNA helicase A in the MEF1 transcription factor complex up-regulates the MDR1 gene in multidrug-resistant cancer cells. J Biol Chem 2004;279:17134–41.[Abstract/Free Full Text]
  61. Bargou RC, Jurchott K, Wagener C, et al. Nuclear localization and increased levels of transcription factor YB-1 in primary human breast cancers are associated with intrinsic MDR1 gene expression. Nat Med 1997;3:447–50.[CrossRef][Medline]
  62. Oda Y, Sakamoto A, Shinohara N, et al. Nuclear expression of YB-1 protein correlates with P-glycoprotein expression in human osteosarcoma. Clin Cancer Res 1998;4:2273–7.[Abstract]
  63. Oda Y, Ohishi Y, Saito T, et al. Nuclear expression of Y-box-binding protein-1 correlates with P-glycoprotein and topoisomerase II{alpha} expression, and with poor prognosis in synovial sarcoma. J Pathol 2003;199:251–8.[CrossRef][Medline]
  64. Saji H, Toi M, Saji S, Koike M, Kohno K, Kuwano M. Nuclear expression of YB-1 protein correlates with P-glycoprotein expression in human breast carcinoma. Cancer Lett 2003;190:191–7.[CrossRef][Medline]
  65. Janz M, Harbeck N, Dettmar P, et al. Y-box factor YB-1 predicts drug resistance and patient outcome in breast cancer independent of clinically relevant tumor biologic factors HER2, uPA and PAI-1. Int J Cancer 2002;97:278–82.[CrossRef][Medline]
  66. Kamura T, Yahata H, Amada S, et al. Is nuclear expression of Y box-binding protein-1 a new prognostic factor in ovarian serous adenocarcinoma? Cancer 1999;85:2450–4.[CrossRef][Medline]
  67. Huang X, Ushijima K, Komai K, et al. Co-expression of Y box-binding protein-1 and P-glycoprotein as a prognostic marker for survival in epithelial ovarian cancer. Gynecol Oncol 2004;93:287–91.[CrossRef][Medline]
  68. Yahata H, Kobayashi H, Kamura T, et al. Increased nuclear localization of transcription factor YB-1 in acquired cisplatin-resistant ovarian cancer. J Cancer Res Clin Oncol 2002;128:621–6.[CrossRef][Medline]
  69. Gimenez-Bonafe P, Fedoruk MN, Whitmore TG, et al. YB-1 is upregulated during prostate cancer tumor progression and increases P-glycoprotein activity. Prostate 2004;59:337–49.[CrossRef][Medline]
  70. Shibao K, Takano H, Nakayama Y, et al. Enhanced coexpression of YB-1 and DNA topoisomerase II{alpha} genes in human colorectal carcinomas. Int J Cancer 1999;83:732–7.[CrossRef][Medline]
  71. Okamoto T, Izumi H, Imamura T, et al. Direct interaction of p53 with the Y-box binding protein, YB-1: a mechanism for regulation of human gene expression. Oncogene 2000;19:6194–202.[CrossRef][Medline]
  72. Ise T, Nagatani G, Imamura T, et al. Transcription factor Y-box binding protein 1 binds preferentially to cisplatin-modified DNA and interacts with proliferating cell nuclear antigen. Cancer Res 1999;59:342–6.[Abstract/Free Full Text]
  73. Levenson VV, Davidovich IA, Roninson IB. Pleiotropic resistance to DNA-interactive drugs is associated with increased expression of genes involved in DNA replication, repair, and stress response. Cancer Res 2000;60:5027–30.[Abstract/Free Full Text]
  74. Yao R, Wang Y, Lubet RA, You M. Differentially expressed genes associated with mouse lung tumor progression. Oncogene 2002;21:5814–21.[CrossRef][Medline]
  75. Ito Y, Yoshida H, Shibahara K, et al. Y-box binding protein expression in thyroid neoplasms: its linkage with anaplastic transformation. Pathol Int 2003;53:429–33.[CrossRef][Medline]
  76. Bader AG, Felts KA, Jiang N, Chang HW, Vogt PK. Y box-binding protein 1 induces resistance to oncogenic transformation by the phosphatidylinositol 3-kinase pathway. Proc Natl Acad Sci U S A 2003;100:12384–9.[Abstract/Free Full Text]
  77. Marenstein DR, Ocampo MT, Chan MK, et al. Stimulation of human endonuclease III by Y box-binding protein 1 (DNA-binding protein B). Interaction between a base excision repair enzyme and a transcription factor. J Biol Chem 2001;276:21242–9.[Abstract/Free Full Text]
  78. Combates NJ, Rzepka RW, Chen YN, Cohen D. NF-IL6, a member of the C/EBP family of transcription factors, binds and trans-activates the human MDR1 gene promoter. J Biol Chem 1994;269:29715–9.[Abstract/Free Full Text]
  79. Chuang SE, Doong SL, Lin MT, Cheng AL. Tax of the human T-lymphotropic virus type I transactivates promoter of the MDR-1 gene. Biochem Biophys Res Commun 1997;238:482–6.[CrossRef][Medline]
  80. Takara K, Takagi K, Tsujimoto M, Ohnishi N, Yokoyama T. Digoxin up-regulates multidrug resistance transporter (MDR1) mRNA and simultaneously downregulates steroid xenobiotic receptor mRNA. Biochem Biophys Res Commun 2003;306:116–20.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Cancer Res.Home page
T. Fujii, A. Kawahara, Y. Basaki, S. Hattori, K. Nakashima, K. Nakano, K. Shirouzu, K. Kohno, T. Yanagawa, H. Yamana, et al.
Expression of HER2 and Estrogen Receptor {alpha} Depends upon Nuclear Localization of Y-Box Binding Protein-1 in Human Breast Cancers
Cancer Res., March 1, 2008; 68(5): 1504 - 1512.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. Shiota, H. Izumi, T. Onitsuka, N. Miyamoto, E. Kashiwagi, A. Kidani, A. Yokomizo, S. Naito, and K. Kohno
Twist Promotes Tumor Cell Growth through YB-1 Expression
Cancer Res., January 1, 2008; 68(1): 98 - 105.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. Uchiumi, A. Fotovati, T. Sasaguri, K. Shibahara, T. Shimada, T. Fukuda, T. Nakamura, H. Izumi, T. Tsuzuki, M. Kuwano, et al.
YB-1 Is Important for an Early Stage Embryonic Development: NEURAL TUBE FORMATION AND CELL PROLIFERATION
J. Biol. Chem., December 29, 2006; 281(52): 40440 - 40449.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L. M. Huff, J.-S. Lee, R. W. Robey, and T. Fojo
Characterization of Gene Rearrangements Leading to Activation of MDR-1
J. Biol. Chem., December 1, 2006; 281(48): 36501 - 36509.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
Z. H. Lu, J. T. Books, and T. J. Ley
YB-1 Is Important for Late-Stage Embryonic Development, Optimal Cellular Stress Responses, and the Prevention of Premature Senescence
Mol. Cell. Biol., June 1, 2005; 25(11): 4625 - 4637.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kuwano, M.
Right arrow Articles by Kohno, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kuwano, M.
Right arrow Articles by Kohno, K.
Related Collections
Right arrow Therapeutics and Targets
Right arrow Therapeutics and Targets: Drug Mechanisms and Resistance

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation