Resistance to Diverse Drugs and Ultraviolet Light Conferred by Overexpression of a Novel Human 26 S Proteasome Subunit

We have investigated the usefulness of the fission yeast Schizosaccharomyces pombe as a model organism for the discovery of novel modes of drug resistance in human cells. In fission yeast, overexpression of the essentialpad1 + gene confers pleiotropic drug resistance through a pathway involving an AP-1 transcription factor encoded bypap1 +. We have identified POH1, a human pad1 homologue that can substitute fully forpad1 + and induce AP-1-dependent drug resistance in fission yeast. POH1 also confers P-glycoprotein-independent resistance to taxol (paclitaxel), doxorubicin, 7-hydroxystaurosporine, and ultraviolet light when transiently overexpressed in mammalian cells. Poh1 is a previously unidentified component of the human 26 S proteasome, a multiprotein complex that degrades proteins targeted for destruction by the ubiquitin pathway. Hence, Poh1 is part of a conserved mechanism that determines cellular susceptibility to cytotoxic agents, perhaps by influencing the ubiquitin-dependent proteolysis of transcription factors. We have investigated the usefulness of the fission yeast Schizosaccharomyces pombe as a model organism for the discovery of novel modes of drug resistance in human cells. In fission yeast, overexpression of the essentialpad1 + gene confers pleiotropic drug resistance through a pathway involving an AP-1 transcription factor encoded bypap1 +. We have identified POH1, a human pad1 homologue that can substitute fully forpad1 + and induce AP-1-dependent drug resistance in fission yeast. POH1 also confers P-glycoprotein-independent resistance to taxol (paclitaxel), doxorubicin, 7-hydroxystaurosporine, and ultraviolet light when transiently overexpressed in mammalian cells. Poh1 is a previously unidentified component of the human 26 S proteasome, a multiprotein complex that degrades proteins targeted for destruction by the ubiquitin pathway. Hence, Poh1 is part of a conserved mechanism that determines cellular susceptibility to cytotoxic agents, perhaps by influencing the ubiquitin-dependent proteolysis of transcription factors. Exposure of eukaryotic cells to any of a wide variety of cytotoxic agents can result in the appearance of multiply resistant subpopulations, a phenomenon that frequently limits the effectiveness of anticancer therapies. Much effort has been directed toward improved understanding of the molecular mechanisms that underlie such pleiotropic resistance. Many of these studies have used mammalian cell lines selected in vitro for their resistance to high concentrations of cytotoxic drugs. Under these circumstances the mechanism of resistance typically involves overexpression of P-glycoprotein (P-gp), 1The abbreviations used are: P-gp, P-glycoprotein; UCN-01, 7-hydroxystaurosporine; HA, hemagglutinin. 1The abbreviations used are: P-gp, P-glycoprotein; UCN-01, 7-hydroxystaurosporine; HA, hemagglutinin. a drug-excluding pump with broad specificity (1Riordan J.R. Deuchars K. Kartner N. Alon N. Trent J. Ling V. Nature. 1985; 316: 817-819Crossref PubMed Scopus (689) Google Scholar, 2Kartner N. Riordan J.R. Ling V. Science. 1983; 221: 1285-1288Crossref PubMed Scopus (875) Google Scholar). Unfortunately, P-gp overexpression fails to account for the majority of clinical drug resistances especially in solid tumors (3Kaye S.B. Am. J. Med. 1995; 99 (6A44S): 6A40SAbstract Full Text PDF Scopus (8) Google Scholar), and the key determinants of this phenomenon remain largely unknown.We have taken an alternative route to the identification of human proteins potentially involved in pleiotropic drug resistance. The fission yeast Schizosaccharomyces pombe is established as a model organism in which powerful genetical approaches can be used to elucidate fundamental but complex eukaryotic processes such as mitosis (4Nurse P. Nature. 1990; 344: 503-508Crossref PubMed Scopus (2216) Google Scholar). Overexpression of the pad1 + gene inS. pombe was recently found to confer moderate resistance to the protein kinase inhibitor staurosporine and a variety of other drugs including caffeine and the spindle poison thiabendazole (5Shimanuki M. Saka Y. Yanagida M. Toda T. J. Cell Sci. 1995; 108: 569-579Crossref PubMed Google Scholar, 6Usui T. Yoshida M. Honda A. Beppu T. Horinouchi S. Gene. 1995; 161: 93-96Crossref PubMed Scopus (13) Google Scholar, 7Kumada K. Yanagida M. Toda T. Mol. Gen. Genet. 1996; 250: 59-68PubMed Google Scholar). We have identified a human functional pad1 homologue (Poh1) that confers moderate resistance to chemotherapeutic drugs and also to ultraviolet light when transiently overproduced in mammalian cells. Poh1 is a previously unidentified component of the 26 S proteasome and genetical data suggest that Poh1-induced drug resistance is mediated through AP-1 transcription factors.DISCUSSIONThe validity of fission yeast as a model organism with which to investigate drug resistance in mammals is confirmed by our demonstration that Pad1, a key determinant of pleiotropic resistance inS. pombe, is functionally conserved as Poh1 in human cells. In COS cells the response to a specific subset of cytotoxic insults is modified by overexpression of POH1 in such a way that cell survival is favored. Alterations in P-gp expression or intracellular drug accumulation do not appear to be involved, but it is not clear at this stage if the POH1-induced survival advantage reflects a decreased propensity for cell death or an alteration in the processing of potentially lethal damage. POH1 can also induce drug resistance in fission yeast, which lacks the apoptotic cell death program, suggesting that modulation of apoptosis is unlikely to be solely responsible for POH1-induced resistance in mammalian cells.Poh1 is a novel component of the 26 S proteasome, indicating that proteolysis is involved in determining the sensitivity of human cells to cytotoxic treatments. A number of recent reports lend weight to this idea. Mutations in the fission yeast proteasome components encoded bymts2 + and mts3 + (21Gordon C. McGurk G. Wallace M. Hastie N.D. J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, C. McGurk G. P. C. Hastie N.D. Nature. PubMed Scopus Google for and confer resistance to the spindle poison at the overexpression of POH1 in fission yeast also resistance to this of human cells was by proteasome Science. 1996; PubMed Scopus Google Scholar). We it that Poh1 drug resistance by modulation of a mammalian proteasome and AP-1 for in drug resistance in fission yeast and the Poh1 and suggest that modulation of transcription underlie the of drug resistance by the Poh1 proteasome overexpression of in fission yeast in a of drug resistance that overexpression of (5Shimanuki M. Saka Y. Yanagida M. Toda T. J. Cell Sci. 1995; 108: 569-579Crossref PubMed Google Scholar, T. M. Yanagida M. PubMed Scopus Google Scholar). be the of AP-1 that induce resistance to cytotoxic and of which to cellular resistance J. Full Text PDF PubMed Google Scholar, S. V. J. PubMed Scopus Google Scholar). in yeast the of the gene has been to be AP-1 Mol. PubMed Google Scholar). gene which the in and can cellular drug resistance. the in yeast of resistance to that mechanisms also M. M. Genet. PubMed Scopus Google Scholar). In with our of P-gp expression POH1 drug resistance in and fission yeast was found to be of drug T. Yoshida M. Honda A. Beppu T. Horinouchi S. Gene. 1995; 161: 93-96Crossref PubMed Scopus (13) Google J. PubMed Google and to be by the pathway A. A. Sci. S. A. PubMed Scopus Google Scholar, M. Full Text PDF PubMed Scopus Google Scholar, C. N. T. A. T. M. K. N. A. K. Mol. 1995; PubMed Scopus Google Scholar, A. A. Mol. 1995; PubMed Scopus Google Scholar), and expression of or other of these AP-1 has been with drug resistance in a number of J. Full Text PDF PubMed Google Scholar, 1995; Google Scholar, PubMed Scopus Google Scholar). of to be in response to by protein kinase M. Science. PubMed Scopus Google Scholar). In cells found to be to M. M. P. J. 1995; PubMed Scopus Google Scholar), was not suggesting a for AP-1 in a pathway that cell survival to a of cytotoxic suggest that a component of the 26 S proteasome, also in such a pathway in mammalian cells. pathway is potentially involved in clinical resistance to anticancer and our data that Poh1 is but in human cell and C. The of the of Poh1 in clinical drug resistance ubiquitin-dependent proteolysis and transcription with the recent of yeast and mammalian as a and as a component of the 26 S proteasome Nature. PubMed Scopus Google Scholar, K. K. S. N. C. K. 1995; PubMed Scopus Google Scholar, C. Nature. 1996; PubMed Scopus Google Scholar). with Sci. S. A. 1996; PubMed Scopus Google and also with a number of transcription of the C. V. P. J. 1996; PubMed Scopus Google Scholar). is not clear at this stage by as a for transcription that have been targeted for ubiquitin-dependent or if the 26 S proteasome component and transcription for other is that the protein which was identified as a M. S. Toda T. M. Nature. 1996; PubMed Scopus Google is a of identified as a component of the 26 S that of proteolysis with be in the modulation of to a wide variety of Exposure of eukaryotic cells to any of a wide variety of cytotoxic agents can result in the appearance of multiply resistant subpopulations, a phenomenon that frequently limits the effectiveness of anticancer therapies. Much effort has been directed toward improved understanding of the molecular mechanisms that underlie such pleiotropic resistance. Many of these studies have used mammalian cell lines selected in vitro for their resistance to high concentrations of cytotoxic drugs. Under these circumstances the mechanism of resistance typically involves overexpression of P-glycoprotein (P-gp), 1The abbreviations used are: P-gp, P-glycoprotein; UCN-01, 7-hydroxystaurosporine; HA, hemagglutinin. 1The abbreviations used are: P-gp, P-glycoprotein; UCN-01, 7-hydroxystaurosporine; HA, hemagglutinin. a drug-excluding pump with broad specificity (1Riordan J.R. Deuchars K. Kartner N. Alon N. Trent J. Ling V. Nature. 1985; 316: 817-819Crossref PubMed Scopus (689) Google Scholar, 2Kartner N. Riordan J.R. Ling V. Science. 1983; 221: 1285-1288Crossref PubMed Scopus (875) Google Scholar). Unfortunately, P-gp overexpression fails to account for the majority of clinical drug resistances especially in solid tumors (3Kaye S.B. Am. J. Med. 1995; 99 (6A44S): 6A40SAbstract Full Text PDF Scopus (8) Google Scholar), and the key determinants of this phenomenon remain largely We have taken an alternative route to the identification of human proteins potentially involved in pleiotropic drug resistance. The fission yeast Schizosaccharomyces pombe is established as a model organism in which powerful genetical approaches can be used to elucidate fundamental but complex eukaryotic processes such as mitosis (4Nurse P. Nature. 1990; 344: 503-508Crossref PubMed Scopus (2216) Google Scholar). Overexpression of the pad1 + gene inS. pombe was recently found to confer moderate resistance to the protein kinase inhibitor staurosporine and a variety of other drugs including caffeine and the spindle poison thiabendazole (5Shimanuki M. Saka Y. Yanagida M. Toda T. J. Cell Sci. 1995; 108: 569-579Crossref PubMed Google Scholar, 6Usui T. Yoshida M. Honda A. Beppu T. Horinouchi S. Gene. 1995; 161: 93-96Crossref PubMed Scopus (13) Google Scholar, 7Kumada K. Yanagida M. Toda T. Mol. Gen. Genet. 1996; 250: 59-68PubMed Google Scholar). We have identified a human functional pad1 homologue (Poh1) that confers moderate resistance to chemotherapeutic drugs and also to ultraviolet light when transiently overproduced in mammalian cells. Poh1 is a previously unidentified component of the 26 S proteasome and genetical data suggest that Poh1-induced drug resistance is mediated through AP-1 transcription factors. validity of fission yeast as a model organism with which to investigate drug resistance in mammals is confirmed by our demonstration that Pad1, a key determinant of pleiotropic resistance inS. pombe, is functionally conserved as Poh1 in human cells. In COS cells the response to a specific subset of cytotoxic insults is modified by overexpression of POH1 in such a way that cell survival is favored. Alterations in P-gp expression or intracellular drug accumulation do not appear to be involved, but it is not clear at this stage if the POH1-induced survival advantage reflects a decreased propensity for cell death or an alteration in the processing of potentially lethal damage. POH1 can also induce drug resistance in fission yeast, which lacks the apoptotic cell death program, suggesting that modulation of apoptosis is unlikely to be solely responsible for POH1-induced resistance in mammalian cells.Poh1 is a novel component of the 26 S proteasome, indicating that proteolysis is involved in determining the sensitivity of human cells to cytotoxic treatments. A number of recent reports lend weight to this idea. Mutations in the fission yeast proteasome components encoded bymts2 + and mts3 + (21Gordon C. McGurk G. Wallace M. Hastie N.D. J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, C. McGurk G. P. C. Hastie N.D. Nature. PubMed Scopus Google for and confer resistance to the spindle poison at the overexpression of POH1 in fission yeast also resistance to this of human cells was by proteasome Science. 1996; PubMed Scopus Google Scholar). We it that Poh1 drug resistance by modulation of a mammalian proteasome and AP-1 for in drug resistance in fission yeast and the Poh1 and suggest that modulation of transcription underlie the of drug resistance by the Poh1 proteasome overexpression of in fission yeast in a of drug resistance that overexpression of (5Shimanuki M. Saka Y. Yanagida M. Toda T. J. Cell Sci. 1995; 108: 569-579Crossref PubMed Google Scholar, T. M. Yanagida M. PubMed Scopus Google Scholar). be the of AP-1 that induce resistance to cytotoxic and of which to cellular resistance J. Full Text PDF PubMed Google Scholar, S. V. J. PubMed Scopus Google Scholar). in yeast the of the gene has been to be AP-1 Mol. PubMed Google Scholar). gene which the in and can cellular drug resistance. the in yeast of resistance to that mechanisms also M. M. Genet. PubMed Scopus Google Scholar). In with our of P-gp expression POH1 drug resistance in and fission yeast was found to be of drug T. Yoshida M. Honda A. Beppu T. Horinouchi S. Gene. 1995; 161: 93-96Crossref PubMed Scopus (13) Google J. PubMed Google and to be by the pathway A. A. Sci. S. A. PubMed Scopus Google Scholar, M. Full Text PDF PubMed Scopus Google Scholar, C. N. T. A. T. M. K. N. A. K. Mol. 1995; PubMed Scopus Google Scholar, A. A. Mol. 1995; PubMed Scopus Google Scholar), and expression of or other of these AP-1 has been with drug resistance in a number of J. Full Text PDF PubMed Google Scholar, 1995; Google Scholar, PubMed Scopus Google Scholar). of to be in response to by protein kinase M. Science. PubMed Scopus Google Scholar). In cells found to be to M. M. P. J. 1995; PubMed Scopus Google Scholar), was not suggesting a for AP-1 in a pathway that cell survival to a of cytotoxic suggest that a component of the 26 S proteasome, also in such a pathway in mammalian cells. pathway is potentially involved in clinical resistance to anticancer and our data that Poh1 is but in human cell and C. The of the of Poh1 in clinical drug resistance ubiquitin-dependent proteolysis and transcription with the recent of yeast and mammalian as a and as a component of the 26 S proteasome Nature. PubMed Scopus Google Scholar, K. K. S. N. C. K. 1995; PubMed Scopus Google Scholar, C. Nature. 1996; PubMed Scopus Google Scholar). with Sci. S. A. 1996; PubMed Scopus Google and also with a number of transcription of the C. V. P. J. 1996; PubMed Scopus Google Scholar). is not clear at this stage by as a for transcription that have been targeted for ubiquitin-dependent or if the 26 S proteasome component and transcription for other is that the protein which was identified as a M. S. Toda T. M. Nature. 1996; PubMed Scopus Google is a of identified as a component of the 26 S that of proteolysis with be in the modulation of to a wide variety of The validity of fission yeast as a model organism with which to investigate drug resistance in mammals is confirmed by our demonstration that Pad1, a key determinant of pleiotropic resistance inS. pombe, is functionally conserved as Poh1 in human cells. In COS cells the response to a specific subset of cytotoxic insults is modified by overexpression of POH1 in such a way that cell survival is favored. Alterations in P-gp expression or intracellular drug accumulation do not appear to be involved, but it is not clear at this stage if the POH1-induced survival advantage reflects a decreased propensity for cell death or an alteration in the processing of potentially lethal damage. POH1 can also induce drug resistance in fission yeast, which lacks the apoptotic cell death program, suggesting that modulation of apoptosis is unlikely to be solely responsible for POH1-induced resistance in mammalian cells. Poh1 is a novel component of the 26 S proteasome, indicating that proteolysis is involved in determining the sensitivity of human cells to cytotoxic treatments. A number of recent reports lend weight to this idea. Mutations in the fission yeast proteasome components encoded bymts2 + and mts3 + (21Gordon C. McGurk G. Wallace M. Hastie N.D. J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, C. McGurk G. P. C. Hastie N.D. Nature. PubMed Scopus Google for and confer resistance to the spindle poison at the overexpression of POH1 in fission yeast also resistance to this of human cells was by proteasome Science. 1996; PubMed Scopus Google Scholar). We it that Poh1 drug resistance by modulation of a mammalian proteasome Poh1 and AP-1 for in drug resistance in fission yeast and the Poh1 and suggest that modulation of transcription underlie the of drug resistance by the Poh1 proteasome overexpression of in fission yeast in a of drug resistance that overexpression of (5Shimanuki M. Saka Y. Yanagida M. Toda T. J. Cell Sci. 1995; 108: 569-579Crossref PubMed Google Scholar, T. M. Yanagida M. PubMed Scopus Google Scholar). be the of AP-1 that induce resistance to cytotoxic and of which to cellular resistance J. Full Text PDF PubMed Google Scholar, S. V. J. PubMed Scopus Google Scholar). in yeast the of the gene has been to be AP-1 Mol. PubMed Google Scholar). gene which the in and can cellular drug resistance. the in yeast of resistance to that mechanisms also M. M. Genet. PubMed Scopus Google Scholar). In with our of P-gp expression POH1 drug resistance in and fission yeast was found to be of drug T. Yoshida M. Honda A. Beppu T. Horinouchi S. Gene. 1995; 161: 93-96Crossref PubMed Scopus (13) Google J. PubMed Google and to be by the pathway A. A. Sci. S. A. PubMed Scopus Google Scholar, M. Full Text PDF PubMed Scopus Google Scholar, C. N. T. A. T. M. K. N. A. K. Mol. 1995; PubMed Scopus Google Scholar, A. A. Mol. 1995; PubMed Scopus Google Scholar), and expression of or other of these AP-1 has been with drug resistance in a number of J. Full Text PDF PubMed Google Scholar, 1995; Google Scholar, PubMed Scopus Google Scholar). of to be in response to by protein kinase M. Science. PubMed Scopus Google Scholar). In cells found to be to M. M. P. J. 1995; PubMed Scopus Google Scholar), was not suggesting a for AP-1 in a pathway that cell survival to a of cytotoxic suggest that a component of the 26 S proteasome, also in such a pathway in mammalian cells. pathway is potentially involved in clinical resistance to anticancer and our data that Poh1 is but in human cell and C. The of the of Poh1 in clinical drug resistance ubiquitin-dependent proteolysis and transcription with the recent of yeast and mammalian as a and as a component of the 26 S proteasome Nature. PubMed Scopus Google Scholar, K. K. S. N. C. K. 1995; PubMed Scopus Google Scholar, C. Nature. 1996; PubMed Scopus Google Scholar). with Sci. S. A. 1996; PubMed Scopus Google and also with a number of transcription of the C. V. P. J. 1996; PubMed Scopus Google Scholar). is not clear at this stage by as a for transcription that have been targeted for ubiquitin-dependent or if the 26 S proteasome component and transcription for other is that the protein which was identified as a M. S. Toda T. M. Nature. 1996; PubMed Scopus Google is a of identified as a component of the 26 S that of proteolysis with be in the modulation of to a wide variety of Poh1 and AP-1 for in drug resistance in fission yeast and the Poh1 and suggest that modulation of transcription underlie the of drug resistance by the Poh1 proteasome overexpression of in fission yeast in a of drug resistance that overexpression of (5Shimanuki M. Saka Y. Yanagida M. Toda T. J. Cell Sci. 1995; 108: 569-579Crossref PubMed Google Scholar, T. M. Yanagida M. PubMed Scopus Google Scholar). be the of AP-1 that induce resistance to cytotoxic and of which to cellular resistance J. Full Text PDF PubMed Google Scholar, S. V. J. PubMed Scopus Google Scholar). in yeast the of the gene has been to be AP-1 Mol. PubMed Google Scholar). gene which the in and can cellular drug resistance. the in yeast of resistance to that mechanisms also M. M. Genet. PubMed Scopus Google Scholar). In with our of P-gp expression POH1 drug resistance in and fission yeast was found to be of drug T. Yoshida M. Honda A. Beppu T. Horinouchi S. Gene. 1995; 161: 93-96Crossref PubMed Scopus (13) Google J. PubMed Google and to be by the pathway A. A. Sci. S. A. PubMed Scopus Google Scholar, M. Full Text PDF PubMed Scopus Google Scholar, C. N. T. A. T. M. K. N. A. K. Mol. 1995; PubMed Scopus Google Scholar, A. A. Mol. 1995; PubMed Scopus Google Scholar), and expression of or other of these AP-1 has been with drug resistance in a number of J. Full Text PDF PubMed Google Scholar, 1995; Google Scholar, PubMed Scopus Google Scholar). of to be in response to by protein kinase M. Science. PubMed Scopus Google Scholar). In cells found to be to M. M. P. J. 1995; PubMed Scopus Google Scholar), was not suggesting a for AP-1 in a pathway that cell survival to a of cytotoxic suggest that a component of the 26 S proteasome, also in such a pathway in mammalian cells. pathway is potentially involved in clinical resistance to anticancer and our data that Poh1 is but in human cell and C. The of the of Poh1 in clinical drug resistance ubiquitin-dependent proteolysis and transcription with the recent of yeast and mammalian as a and as a component of the 26 S proteasome Nature. PubMed Scopus Google Scholar, K. K. S. N. C. K. 1995; PubMed Scopus Google Scholar, C. Nature. 1996; PubMed Scopus Google Scholar). with Sci. S. A. 1996; PubMed Scopus Google and also with a number of transcription of the C. V. P. J. 1996; PubMed Scopus Google Scholar). is not clear at this stage by as a for transcription that have been targeted for ubiquitin-dependent or if the 26 S proteasome component and transcription for other is that the protein which was identified as a M. S. Toda T. M. Nature. 1996; PubMed Scopus Google is a of identified as a component of the 26 S that of proteolysis with be in the modulation of to a wide variety of Poh1 and AP-1 for in drug resistance in fission yeast and the Poh1 and suggest that modulation of transcription underlie the of drug resistance by the Poh1 proteasome overexpression of in fission yeast in a of drug resistance that overexpression of (5Shimanuki M. Saka Y. Yanagida M. Toda T. J. Cell Sci. 1995; 108: 569-579Crossref PubMed Google Scholar, T. M. Yanagida M. PubMed Scopus Google Scholar). be the of AP-1 that induce resistance to cytotoxic and of which to cellular resistance J. Full Text PDF PubMed Google Scholar, S. V. J. PubMed Scopus Google Scholar). in yeast the of the gene has been to be AP-1 Mol. PubMed Google Scholar). gene which the in and can cellular drug resistance. the in yeast of resistance to that mechanisms also M. M. Genet. PubMed Scopus Google Scholar). In with our of P-gp expression POH1 drug resistance in and fission yeast was found to be of drug T. Yoshida M. Honda A. Beppu T. Horinouchi S. Gene. 1995; 161: 93-96Crossref PubMed Scopus (13) Google J. PubMed Google and to be by the pathway A. A. Sci. S. A. PubMed Scopus Google Scholar, M. Full Text PDF PubMed Scopus Google Scholar, C. N. T. A. T. M. K. N. A. K. Mol. 1995; PubMed Scopus Google Scholar, A. A. Mol. 1995; PubMed Scopus Google Scholar), and expression of or other of these AP-1 has been with drug resistance in a number of J. Full Text PDF PubMed Google Scholar, 1995; Google Scholar, PubMed Scopus Google Scholar). of to be in response to by protein kinase M. Science. PubMed Scopus Google Scholar). In cells found to be to M. M. P. J. 1995; PubMed Scopus Google Scholar), was not suggesting a for AP-1 in a pathway that cell survival to a of cytotoxic suggest that a component of the 26 S proteasome, also in such a pathway in mammalian cells. pathway is potentially involved in clinical resistance to anticancer and our data that Poh1 is but in human cell and C. The of the of Poh1 in clinical drug resistance ubiquitin-dependent proteolysis and transcription with the recent of yeast and mammalian as a and as a component of the 26 S proteasome Nature. PubMed Scopus Google Scholar, K. K. S. N. C. K. 1995; PubMed Scopus Google Scholar, C. Nature. 1996; PubMed Scopus Google Scholar). with Sci. S. A. 1996; PubMed Scopus Google and also with a number of transcription of the C. V. P. J. 1996; PubMed Scopus Google Scholar). is not clear at this stage by as a for transcription that have been targeted for ubiquitin-dependent or if the 26 S proteasome component and transcription for other is that the protein which was identified as a M. S. Toda T. M. Nature. 1996; PubMed Scopus Google is a of identified as a component of the 26 S that of proteolysis with be in the modulation of to a wide variety of The for in drug resistance in fission yeast and the Poh1 and suggest that modulation of transcription underlie the of drug resistance by the Poh1 proteasome overexpression of in fission yeast in a of drug resistance that overexpression of (5Shimanuki M. Saka Y. Yanagida M. Toda T. J. Cell Sci. 1995; 108: 569-579Crossref PubMed Google Scholar, T. M. Yanagida M. PubMed Scopus Google Scholar). be the of AP-1 that induce resistance to cytotoxic and of which to cellular resistance J. Full Text PDF PubMed Google Scholar, S. V. J. PubMed Scopus Google Scholar). in yeast the of the gene has been to be AP-1 Mol. PubMed Google Scholar). gene which the in and can cellular drug resistance. the in yeast of resistance to that mechanisms also M. M. Genet. PubMed Scopus Google Scholar). In with our of P-gp expression POH1 drug resistance in and fission yeast was found to be of drug T. Yoshida M. Honda A. Beppu T. Horinouchi S. Gene. 1995; 161: 93-96Crossref PubMed Scopus (13) Google J. PubMed Google Scholar). and to be by the pathway A. A. Sci. S. A. PubMed Scopus Google Scholar, M. Full Text PDF PubMed Scopus Google Scholar, C. N. T. A. T. M. K. N. A. K. Mol. 1995; PubMed Scopus Google Scholar, A. A. Mol. 1995; PubMed Scopus Google Scholar), and expression of or other of these AP-1 has been with drug resistance in a number of J. Full Text PDF PubMed Google Scholar, 1995; Google Scholar, PubMed Scopus Google Scholar). of to be in response to by protein kinase M. Science. PubMed Scopus Google Scholar). In cells found to be to M. M. P. J. 1995; PubMed Scopus Google Scholar), was not suggesting a for AP-1 in a pathway that cell survival to a of cytotoxic suggest that a component of the 26 S proteasome, also in such a pathway in mammalian cells. pathway is potentially involved in clinical resistance to anticancer and our data that Poh1 is but in human cell and C. The of the of Poh1 in clinical drug resistance A ubiquitin-dependent proteolysis and transcription with the recent of yeast and mammalian as a and as a component of the 26 S proteasome Nature. PubMed Scopus Google Scholar, K. K. S. N. C. K. 1995; PubMed Scopus Google Scholar, C. Nature. 1996; PubMed Scopus Google Scholar). with Sci. S. A. 1996; PubMed Scopus Google and also with a number of transcription of the C. V. P. J. 1996; PubMed Scopus Google Scholar). is not clear at this stage by as a for transcription that have been targeted for ubiquitin-dependent or if the 26 S proteasome component and transcription for other is that the protein which was identified as a M. S. Toda T. M. Nature. 1996; PubMed Scopus Google is a of identified as a component of the 26 S that of proteolysis with be in the modulation of to a wide variety of We for C. and M. for to for human for UCN-01, and and for and the