Transcriptional Repression of the Prosurvival Endoplasmic Reticulum Chaperone GRP78/BIP by E2F1

The endoplasmic reticulum chaperone GRP78/BIP plays a central role in the prosurvival machinery, and its enhanced expression has been implicated in drug resistance, carcinogenesis, and metastasis. E2F1, as part of an antitumor safeguard mechanism, promotes apoptosis regardless of functional p53. Using cells that are defective in p53, we show that E2F1 represses GRP78/BIP at the transcriptional level, and this requires its DNA binding domain. Analysis of human GRP78/BIP promoter reporter constructs revealed that the region between -371 and -109 of the proximal promoter contains major E2F1-responsive elements. Toward understanding the underlying mechanism of this regulation, we performed chromatin immunoprecipitation and gel shift assays, demonstrating that E2F1 directly binds to GC-rich regions in the distal GC-box and endoplasmic reticulum stress response element -126 by interfering with the binding of positive regulatory proteins Sp1 and TFII-I of the ER stress response element-binding factor complex. We further show that TFII-I, which is required for optimal stress induction of GRP78/BIP, is suppressed by E2F1 on the protein level. Finally, our studies suggest a molecular link between the inhibition of GRP78/BIP and E2F1-mediated chemosensitization of tumor cells, underscoring its relevance for cancer treatment. Together, the data provide a new mechanism for the incompletely understood tumor suppressor function of E2F1. The endoplasmic reticulum chaperone GRP78/BIP plays a central role in the prosurvival machinery, and its enhanced expression has been implicated in drug resistance, carcinogenesis, and metastasis. E2F1, as part of an antitumor safeguard mechanism, promotes apoptosis regardless of functional p53. Using cells that are defective in p53, we show that E2F1 represses GRP78/BIP at the transcriptional level, and this requires its DNA binding domain. Analysis of human GRP78/BIP promoter reporter constructs revealed that the region between -371 and -109 of the proximal promoter contains major E2F1-responsive elements. Toward understanding the underlying mechanism of this regulation, we performed chromatin immunoprecipitation and gel shift assays, demonstrating that E2F1 directly binds to GC-rich regions in the distal GC-box and endoplasmic reticulum stress response element -126 by interfering with the binding of positive regulatory proteins Sp1 and TFII-I of the ER stress response element-binding factor complex. We further show that TFII-I, which is required for optimal stress induction of GRP78/BIP, is suppressed by E2F1 on the protein level. Finally, our studies suggest a molecular link between the inhibition of GRP78/BIP and E2F1-mediated chemosensitization of tumor cells, underscoring its relevance for cancer treatment. Together, the data provide a new mechanism for the incompletely understood tumor suppressor function of E2F1. Resistance to chemotherapy remains a major obstacle for the treatment of malignant tumors. The complexity of drug resistance in human cancer strongly suggests the involvement of multiple pathways. One mechanism, both intrinsic and acquired, is the result of genetic alterations within cancer cells. Another mechanism may result from environmental conditions that occur naturally in solid tumors (1Brown J.M. Giaccia A.J. Cancer Res. 1998; 58: 1408-1416PubMed Google Scholar). Hypoxia and glucose starvation caused by poor vascularization of tumors represent physiological endoplasmic reticulum (ER) 4The abbreviations used are: ER, endoplasmic reticulum; ERSE, ER stress response element; 4-OHT, 4-hydroxytamoxifen; TA, transactivation; Rb, retinoblastoma protein. stress activating the unfolded protein response (2Feldman D.E. Chauhan V. Koong A.C. Mol. Cancer Res. 2005; 3: 597-605Crossref PubMed Scopus (254) Google Scholar, 3Ni M. Lee A.S. FEBS Lett. 2007; 581: 3641-3651Crossref PubMed Scopus (650) Google Scholar). A major unfolded protein response target is GRP78 (glucose-regulated protein 78), also known as BIP, whose induction is critical for control of protein folding and assembly, targeting of misfolded proteins for proteasome degradation, ER Ca2+ binding, and regulation of the activity of ER stress transducers, such as IRE1, PERK, and ATF6, through a binding-release mechanism (4Haze K. Okada T. Yoshida H. Yanagi H. Yura T. Negishi M. Mori K. Biochem. J. 2001; 355: 19-28Crossref PubMed Scopus (201) Google Scholar, 5Wang Y. Shen J. Arenzana N. Tirasophon W. Kaufman R.J. Prywes R. J. Biol. Chem. 2000; 275: 27013-27020Abstract Full Text Full Text PDF PubMed Google Scholar, 6Okada T. Yoshida H. Akazawa R. Negishi M. Mori K. Biochem. J. 2002; 366: 585-594Crossref PubMed Scopus (414) Google Scholar). GRP78/BIP also acts as an apoptotic regulator by protecting cells against ER stress-induced cell death. Overexpression of GRP78/BIP blocks cleavage of procaspase-7 and -12 in its active form, inhibits stimulation of proapoptotic proteins of the Bcl-2 family, such as BIK and BAX, and prevents cytochrome c release from the mitochondria (7Fu Y. Li J. Lee A.S. Cancer Res. 2007; 67: 3734-3740Crossref PubMed Scopus (255) Google Scholar). GRP78/BIP is highly up-regulated in various cancer cells and human tumors, including breast, lung, liver, prostate, colon, and gastric cancers, correlating with malignancy, metastasis, and drug resistance (8Daneshmand S. Quek M.L. Lin E. Lee C. Cote R.J. Hawes D. Cai J. Groshen S. Lieskovsky G. Skinner D.G. Lee A.S. Pinski J. Hum. Pathol. 2007; 38: 1547-1552Crossref PubMed Scopus (195) Google Scholar, 9Lee E. Nichols P. Spicer D. Groshen S. Yu M.C. Lee A.S. Cancer Res. 2006; 66: 7849-7853Crossref PubMed Scopus (255) Google Scholar). Suppression of GRP78/BIP through small interfering RNA sensitizes human cancer cells to chemotherapeutic drug-mediated cell death and inhibits tumor progression in vivo (10Dong D. Ko B. Baumeister P. Swenson S. Costa F. Markland F. Stiles C. Patterson J.B. Bates S.E. Lee A.S. Cancer Res. 2005; 65: 5785-5791Crossref PubMed Scopus (140) Google Scholar, 11Sugawara S. Takeda K. Lee A. Dennert G. Cancer Res. 1993; 53: 6001-6005PubMed Google Scholar). The intensity of GRP78/BIP expression is generally associated with survival and clinical recurrence in prostate cancer patients (8Daneshmand S. Quek M.L. Lin E. Lee C. Cote R.J. Hawes D. Cai J. Groshen S. Lieskovsky G. Skinner D.G. Lee A.S. Pinski J. Hum. Pathol. 2007; 38: 1547-1552Crossref PubMed Scopus (195) Google Scholar). Thus, inhibition of GRP78/BIP expression represents a novel goal for successful cancer treatment. The ER stress-induced activation of GRP78/BIP is primarily mediated by multiple copies of the ER stress response element (ERSE) with a consensus sequence of CCAAT(N9)CCACG located upstream of the TATA element, although part of the response may also be attributed to ERSE-independent pathways (12Roy B. Lee A.S. Nucleic Acids Res. 1999; 27: 1437-1443Crossref PubMed Scopus (216) Google Scholar). Interaction of NF-Y/CBF and YY1 with the two end-flanking motifs of the ERSE has been well characterized (13Li W.W. Hsiung Y. Zhou Y. B. Lee A.S. Mol. Biol. PubMed Scopus Google Scholar, K. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The sequence in which is required for is GC-rich (12Roy B. Lee A.S. Nucleic Acids Res. 1999; 27: 1437-1443Crossref PubMed Scopus (216) Google Scholar, R. T. Baumeister P. B. V. Lee A.S. Mol. Biol. 2001; PubMed Scopus Google Scholar). proteins the region and with motifs in and stress-induced cells M. S. S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). of ER stress is by cleavage of to ATF6, a factor that with proteins (4Haze K. Okada T. Yoshida H. Yanagi H. Yura T. Negishi M. Mori K. Biochem. J. 2001; 355: 19-28Crossref PubMed Scopus (201) Google Scholar, H. Okada T. K. Yanagi H. Yura T. Negishi M. Mori K. Mol. Biol. 2000; PubMed Scopus Google Scholar, H. Okada T. K. Yanagi H. Yura T. Negishi M. Mori K. Mol. Biol. 2001; PubMed Scopus Google Scholar). TFII-I is also by ER stress and with to a part of the M. Lin J.M. Baumeister P. S. Lee A.S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). studies that stimulation of ERSE by requires its with TFII-I and binding to the sequence within the region R. T. Baumeister P. B. V. Lee A.S. Mol. Biol. 2001; PubMed Scopus Google Scholar). on the data by M. S. S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google is that proteins may function to the of the and TFII-I with ER stress The factor E2F1 plays a critical role in the control of cell progression by the expression of required for the from to A that cell through the is the retinoblastoma protein binds to E2F1 and prevents its E2F1 activity to cell which is of the of E2F1 also apoptosis and and this is an mechanism for DNA to of E2F1 and its by and and by D. H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. R. M. E. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). activation of various apoptosis E2F1 sensitizes cells to apoptosis inhibition of survival mediated by Bcl-2 and its R. Y. 2002; PubMed Scopus Google Scholar, G. J. 2001; PubMed Scopus Google Scholar, M. C. P. 2002; PubMed Scopus Google Scholar). The in Bcl-2 and of the the of E2F1 in human tumors, its apoptotic and suggest that E2F1 may an role in enhanced of malignant cells to cell death. we performed a to proteins associated with E2F1 activity in cells M. S. N. 2006; PubMed Scopus Google Scholar). revealed that E2F1 the protein of the molecular mechanism underlying the of GRP78/BIP by E2F1 in malignant cells functional p53, we the promoter region for factor binding and that of GRP78/BIP by E2F1 at the transcriptional binding to between and and between -126 and of the distal ERSE element, interfering with DNA binding of Sp1 and We also that protein expression of the factor TFII-I, which is required for stress-induced of the GRP78/BIP is in response to E2F1 our data provide that of GRP78/BIP by E2F1 is of the underlying of E2F1-mediated of cancer cells to and and cell in with and used at a of cells to performed with and been T. 2000; PubMed Scopus Google Scholar). in cells, by and by at of that of cell of for for for E2F1, the DNA E2F1 and the the been T. 2000; PubMed Scopus Google Scholar). GRP78/BIP promoter from DNA from cells and the to of the used for of the promoter are in activity a reporter and to protein in cell performed on RNA by an of RNA and performed as S. Takeda K. Lee A. Dennert G. Cancer Res. 1993; 53: 6001-6005PubMed Google Scholar). A of performed to a within the are in in and cell on and to with the and The chromatin immunoprecipitation performed on cells in the of to DNA at a of for at The by to a of for E2F1 Sp1 TFII-I control at with chromatin from the in and for The DNA by are in The on and by in a with the to the of shift with from cells to the GC-box element to and ERSE element to in the GRP78/BIP performed with of and in for at assays, the DNA to the of the The E2F1 binding of the promoter to Y. N. M. H. S. H. M. Y. M. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google used as a positive by on an The on and to are in of cells with with and at with of with in of A and for and to a by The as an of the apoptotic cell by E2F1 to of GRP78/BIP cancer cells of the tumor suppressor in apoptosis pathways. The of E2F1 on tumor which cell death regardless of the has been in of human the of E2F1 on GRP78/BIP expression in cancer cells, and cells with at a of which The in which is by to the has been to cell death of human tumor cells with in apoptotic pathways. used as both cell of GRP78/BIP at E2F1 induction with in cells E2F1, that E2F1-mediated of GRP78/BIP of the and of GRP78/BIP expression with the of E2F1 to proapoptotic such as this we E2F1-mediated apoptosis The of E2F1 on GRP78/BIP further in cells with the which contains the proximal to of the human GRP78/BIP Overexpression of E2F1 in a inhibition of the promoter that regulation of GRP78/BIP expression by E2F1 at the transcriptional level. A E2F1-mediated promoter also ER stress conditions treatment. the promoter T. 2000; PubMed Scopus Google in response to enhanced E2F1 expression The DNA of E2F1 in Full of the GRP78/BIP studies various E2F1 that of such as Bcl-2 and its by E2F1 is on its DNA binding activity R. Y. 2002; PubMed Scopus Google Scholar, J. T. F. K. C. Res. PubMed Scopus Google Scholar, S. T. K. PubMed Scopus Google Scholar). the binding the DNA binding of E2F1 is required for the activity on GRP78/BIP the E2F1 defective and with a in the DNA binding for to GRP78/BIP with the E2F1 expression of activity by of the E2F1 the DNA binding domain. of the at of the of cell that cells the of the GRP78/BIP protein with cells, expression of E2F1 and associated with expression of data that the DNA binding of E2F1 is required for the on the GRP78/BIP of GRP78/BIP for E2F1-mediated is the of a of by GC-rich motifs (12Roy B. Lee A.S. Nucleic Acids Res. 1999; 27: 1437-1443Crossref PubMed Scopus (216) Google Scholar). The human GRP78/BIP promoter contains ER stress response elements. studies the promoter for its response to ER stress revealed that part of its activity is by ERSE-independent pathways. the promoter region to E2F1, a of reporter the proximal -371 to promoter with by GC-rich and ERSE and of E2F1 in cells. in the of promoter activity with the constructs to and to of the the to E2F1, which in the suggest that the region between -371 and -109 of the proximal GRP78/BIP promoter contains the major E2F1-responsive elements. protein expression of E2F1 by E2F1 the GRP78/BIP in and Interaction with Sp1 and TFII-I immunoprecipitation performed to the in vivo binding of E2F1 to the GRP78/BIP Analysis of the promoter region to E2F1 revealed in the -371 to region and a GC-rich element within the ERSE which represent Sp1 binding we two DNA binding located in to the distal GC-box to and a in the ERSE element to as part of the GC-rich cells that the protein used to E2F1 activation through M. S. N. 2006; PubMed Scopus Google Scholar, J. T. M. Nucleic Acids Res. 2002; PubMed Scopus Google Scholar). of cells by of E2F1 by the of for with against E2F1 and DNA by that a region of the GRP78/BIP promoter the and regions which revealed in response to E2F1, to the distal consensus ERSE as a positive the E2F1 binding region of the promoter Y. N. M. H. S. H. M. Y. M. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google The chromatin immunoprecipitation a in E2F1 binding to GRP78/BIP with its binding to the consensus with the reporter the of E2F1 on the promoter through regions the binding of E2F1 to the region with the ERSE on the binding of E2F1 in cells. from various ER a which two motifs that NF-Y/CBF and YY1 and a central sequence that in studies that the GC-rich which binds TFII-I R. T. Baumeister P. B. V. Lee A.S. Mol. Biol. 2001; PubMed Scopus Google also with proteins both in and cells, in GRP78/BIP activation M. S. S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). E2F1 is of promoter activity through Sp1 binding D. S. Mol. Biol. PubMed Scopus Google Scholar, J. H. E. Mol. Biol. PubMed Scopus Google Scholar). to the role of the sequence in E2F1-mediated of the GRP78/BIP we binding of E2F1 with of the transcriptional Sp1 of with against Sp1 and of the region revealed a in the intensity of the activation of E2F1. We also a binding of TFII-I in cells with 4-OHT, which binds directly to the within the region of the ERSE and is required for stimulation of ERSE by R. T. Baumeister P. B. V. Lee A.S. Mol. Biol. 2001; PubMed Scopus Google Scholar). suggest that E2F1 its on GRP78/BIP expression by with the GC-rich region of the distal ERSE through interfering with the binding of positive regulatory such as Sp1 and the distal GC-box in to the Sp1 binding region of the ERSE element a of GRP78/BIP binding of the E2F1 protein to both regions in gel shift to the E2F1 between and and between -126 and A between the from the GRP78/BIP promoter and a from the promoter to E2F1 Y. N. M. H. S. H. M. Y. M. J. Biol. 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Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). to the of factor by binding of E2F1 to the ERSE we the of E2F1 on protein expression of in the regulation of GRP78/BIP transcriptional activity in cells. of the by and treatment with a of GRP78/BIP by E2F1, enhanced of the factor GRP78/BIP on the protein level. The also show that the enhanced E2F1 activity is associated with TFII-I expression and of the expression of and of GRP78/BIP by E2F1 to E2F1-mediated of Cancer to cancer cells are to E2F1 has been to and its various cancer cells to chemotherapeutic the molecular that the between E2F1 and DNA by in human are this has been that expression of GRP78/BIP A. J. S. M.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google which to resistance of tumor cells against this E2F1-mediated of GRP78/BIP promotes drug cells with and with the of cells with E2F1 has GRP78/BIP and a of apoptotic cells with GRP78/BIP expression the of apoptotic cells by E2F1 with and enhanced cell death in the GRP78/BIP our data that enhanced apoptosis induction by treatment with E2F1 and with expression of GRP78/BIP, that of GRP78/BIP by E2F1 is critical for E2F1-mediated chemosensitization of cells. of resistance to chemotherapy is a major obstacle to successful cancer treatment. and glucose to the poor vascularization in the of human solid tumors to the activation of unfolded protein response as a survival mechanism of the the known ER GRP78/BIP to a major role in this prosurvival machinery, which in resistance, cancer and M. Lee A.S. FEBS Lett. 2007; 581: 3641-3651Crossref PubMed Scopus (650) Google Scholar, G. J. Lee A.S. Cancer Res. 1999; PubMed Scopus Google Scholar). 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We E2F1 as major of the prosurvival factor GRP78/BIP in cancer cells. and activation of E2F1 to a in GRP78/BIP and protein expression by of the GRP78/BIP with studies the for E2F1 to cell we that of GRP78/BIP promoter activity by E2F1 requires DNA binding and from data that two regions of the proximal promoter between -371 and and between and -109 the distal GC-box and the ER stress response element which promoter are for the of E2F1. Using promoter constructs in chromatin immunoprecipitation and gel shift assays, we show that E2F1 to the GRP78/BIP promoter both in and in vivo that the distal GC-box and a within the of the GC-rich in ERSE binding of E2F1 to this is by the of the Sp1 and TFII-I from as by mechanism to be from regulation of the two known of E2F1, Bcl-2 and its transcriptional by E2F1 a E2F1 regulatory element R. Y. 2002; PubMed Scopus Google Scholar). Sp1 has generally been to regulation by E2F1 D. S. Mol. Biol. PubMed Scopus Google Scholar, J. H. E. Mol. Biol. 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Full Text Full Text PDF PubMed Scopus Google that in the role of is to this the of activation is by the promoter requires with for binding to promoter DNA to the E2F1 in an E2F1 promoter is to our suggest that E2F1, from its on the GRP78/BIP also GRP78/BIP expression by the protein of of the complex. our the factor TFII-I YY1 in response to E2F1 The protein plays a role in various as and of of and also the GRP78/BIP promoter ER stress conditions P. S. G. E. Y. Lee A.S. Mol. Biol. 2005; PubMed Scopus Google Scholar). Analysis of the YY1 promoter revealed at binding for E2F1 B. S. M. C. E. Biochem. J. 2007; PubMed Scopus Google Scholar). between YY1 and E2F1 in the regulation of the promoter S. S. K. M. Biochem. Res. PubMed Scopus Google the of YY1 protein activation of E2F1-mediated A of YY1 by E2F1, the activity of E2F1 on the GRP78/BIP E2F1-mediated of TFII-I may an role for induction of cell and TFII-I is in response to and cell from TFII-I is and for J. T. Lee C. N. C. Mol. Biol. 2005; PubMed Scopus Google Scholar). has been that this mechanism is and our been performed in cells, this has to be further studies that E2F1 expression to and cell death by apoptosis in a of human cancer cells J. M. G. M.C. Cancer Res. Google Scholar, J. C. R. 1998; PubMed Scopus Google Scholar, M. Y. Cancer 1999; PubMed Scopus Google Scholar, F. T. S. Cancer Res. 2001; Google Scholar, C. A. Cancer Res. 1999; Google Scholar). is that of the apoptotic is by an between the mitochondria and the ER R. M. K. S. 2006; PubMed Scopus Google that the ER apoptosis by mitochondria to and intrinsic S. H. M. V. G. D.E. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). this E2F1 acts by apoptotic a death that the release of cytochrome c from the regardless of through both induction of proapoptotic and of Bcl-2 in tumor cells R. Y. 2002; PubMed Scopus Google Scholar, G. J. 2001; PubMed Scopus Google Scholar, J. Mol. 2007; PubMed Scopus Google Scholar). the of GRP78/BIP that prevents cytochrome c release is mechanism for apoptosis that E2F1 is for E2F1 has been of various cancer cells to treatment P. J. 1999; Google Scholar, Cancer Res. 2002; Google Scholar, C. A. Biol. 2002; PubMed Scopus Google although the mechanism of this is in studies suggest that GRP78/BIP in malignant cells E. Nichols P. Spicer D. Groshen S. Yu M.C. Lee A.S. Cancer Res. 2006; 66: 7849-7853Crossref PubMed Scopus (255) Google Scholar, P. Lee A.S. Cancer Res. 2007; 67: PubMed Scopus Google Scholar). Thus, we characterized the of GRP78/BIP expression by E2F1 as a in the progression of cells we show that the in GRP78/BIP directly with enhanced apoptosis of cells. Together, our suggest that GRP78/BIP is a critical target of E2F1, whose may its to apoptosis and to of tumor cells to We for with