Key points are not available for this paper at this time.
The tumor suppressor p53 functions as a transcriptional activator to induce cell cycle arrest and apoptosis in response to DNA damage. Although p53 was also shown to mediate apoptosis in a manner independent of its transactivation activity, the mechanism and conditions that trigger such cell death have remained largely unknown. We have now shown that inhibition of RNA polymerase II-mediated transcription by α-amanitin or RNA interference induced p53-dependent apoptosis. Inhibition of pol II-mediated transcription resulted in down-regulation of p21Cip1, which was caused by both transcriptional suppression and protein degradation, despite eliciting p53 accumulation, allowing the cells to progress into S phase and then to undergo apoptosis. This cell death did not require the transcription of p53 target genes and was preceded by translocation of the accumulated p53 to mitochondria. Our data thus suggested that blockade of pol II-mediated transcription induced p53 accumulation in mitochondria and was the critical factor for eliciting p53-dependent but transcription-independent apoptosis. The tumor suppressor p53 functions as a transcriptional activator to induce cell cycle arrest and apoptosis in response to DNA damage. Although p53 was also shown to mediate apoptosis in a manner independent of its transactivation activity, the mechanism and conditions that trigger such cell death have remained largely unknown. We have now shown that inhibition of RNA polymerase II-mediated transcription by α-amanitin or RNA interference induced p53-dependent apoptosis. Inhibition of pol II-mediated transcription resulted in down-regulation of p21Cip1, which was caused by both transcriptional suppression and protein degradation, despite eliciting p53 accumulation, allowing the cells to progress into S phase and then to undergo apoptosis. This cell death did not require the transcription of p53 target genes and was preceded by translocation of the accumulated p53 to mitochondria. Our data thus suggested that blockade of pol II-mediated transcription induced p53 accumulation in mitochondria and was the critical factor for eliciting p53-dependent but transcription-independent apoptosis. Apoptosis is a genetically controlled mechanism of cell death that is essential for the elimination of unwanted cells during normal development and for the maintenance of tissue homeostasis. The tumor suppressor protein p53 induces either cell cycle arrest or apoptosis in response to a variety of cellular stresses, including DNA damage, oncogene activation, and hypoxia (1Oren M. Semin. Cancer Biol. 1994; 5: 221-227PubMed Google Scholar, 2Ko L.J. Prives C. Genes Dev. 1996; 10: 1054-1072Crossref PubMed Scopus (2301) Google Scholar, 3Levine A.J. Cell. 1997; 88: 323-331Abstract Full Text Full Text PDF PubMed Scopus (6805) Google Scholar). Loss of p53 function therefore results in failure to remove damaged cells and contributes both to tumor development and to the resistance of cancer cells to therapies based on the induction of DNA damage. It is well established that p53 is a transcriptional regulator and that p53-mediated apoptosis in response to DNA damage is predominantly attributable both to the transcriptional activation of genes that encode apoptotic effectors, such as the BH3-only proteins Noxa and PUMA, Bax, p53AIP1, and PERP (4Oda E. Ohki R. Murasawa H. Nemoto J. Shibue T. Yamashita T. Tokino T. Taniguchi T. Tanaka N. Science. 2000; 288: 1053-1058Crossref PubMed Scopus (1731) Google Scholar, 5Miyashita T. Reed J.C. Cell. 1995; 80: 293-299Abstract Full Text PDF PubMed Scopus (305) Google Scholar, 6Oda K. Arakawa H. Tanaka T. Matsuda K. Tanikawa C. Mori T. Nishimori H. Tamai K. Tokino T. Nakamura Y. Taya Y. Cell. 2000; 102: 849-862Abstract Full Text Full Text PDF PubMed Scopus (1031) Google Scholar, 7Yu J. Zhang L. Hwang P.M. Kinzler K.W. Vogelstein B. Mol. Cell. 2001; 7: 673-682Abstract Full Text Full Text PDF PubMed Scopus (1109) Google Scholar, 8Nakano K. Vousden K.H. Mol. Cell. 2001; 7: 683-694Abstract Full Text Full Text PDF PubMed Scopus (1921) Google Scholar, 9Attardi L.D. Reczek E.E. Cosmas C. Demicco E.G. McCurrach M.E. Lowe S.W. Jacks T. Genes Dev. 2000; 14: 704-718PubMed Google Scholar), as well as to the transcriptional repression of genes for antiapoptotic proteins such as Bcl-2 (10Shen Y. Shenk T. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 8940-8944Crossref PubMed Scopus (142) Google Scholar) and survivin (11Hoffman W.H. Biade S. Zilfou J.T. Chen J. Murphy M. J. Biol. Chem. 2002; 277: 3247-3257Abstract Full Text Full Text PDF PubMed Scopus (711) Google Scholar). In addition to such transcriptional regulation, however, recent evidence has suggested the existence of a transcription-independent pathway of p53-mediated apoptosis (12Caelles C. Helmberg A. Karin M. Nature. 1994; 370: 220-223Crossref PubMed Scopus (843) Google Scholar, 13Haupt Y. Rowan S. Shaulian E. Vousden K.H. Oren M. Genes Dev. 1995; 9: 2170-2183Crossref PubMed Scopus (522) Google Scholar). A fraction of the p53 molecules that accumulate in damaged cells translocates to mitochondria, and this translocation is sufficient for p53 to induce permeabilization of the outer mitochondrial membrane through formation of complexes with the protective proteins Bcl-xL and Bcl-2, resulting in the release of cytochrome c into the cytosol (14Marchenko N.D. Zaika A. Moll U.M. J. Biol. Chem. 2000; 275: 16202-16212Abstract Full Text Full Text PDF PubMed Scopus (790) Google Scholar, 15Mihara M. Erster S. Zaika A. Petrenko O. Chittenden T. Pancoska P. Moll U.M. Mol. Cell. 2003; 11: 577-590Abstract Full Text Full Text PDF PubMed Scopus (1496) Google Scholar). The mechanism by which the relative activities of the transcription-dependent and transcription-independent pathways of p53-mediated apoptosis are regulated, however, has remained unclear. Lesions in the transcribed strand of DNA induced by high concentrations of chemotherapeutic agents such as cisplatin or by high doses of UV radiation trigger the ubiquitination and consequent degradation of the large subunit (LS) 1The abbreviations used are: LS, large subunit; CDK, cyclin-dependent kinase; DSB, DNA double-strand break; PCNA, proliferating-cell nuclear antigen; PI, propidium iodide; pol II, RNA polymerase II; pRb, retinoblastoma protein; BrdUrd, bromodeoxyuridine; siRNA, small interfering RNAs; RNAi, RNA interference; Z, benzyloxycarbonyl; fmk, fluoromethyl ketone; PBS, phosphate-buffered saline; TBS, Tris-buffered saline; mAb, monoclonal antibody; RT, reverse transcription; ATM, ataxia telangiectasia-mutated; ATR, ATM and Rad3-related. of RNA polymerase II (pol II), resulting in transcriptional collapse and the recruitment of DNA repair proteins (16Luo Z. Zheng J. Lu Y. Bregman D.B. Mutat. Res. 2001; 486: 259-274Crossref PubMed Scopus (62) Google Scholar, 17Lee K.B. Wang D. Lippard S.J. Sharp P.A. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4239-4244Crossref PubMed Scopus (154) Google Scholar). A prolonged blockage of pol II-dependent transcription caused by failure to repair such DNA lesions results in cell death by apoptosis (18Friedberg E. Walker G. Siede W. DNA Repair and Mutagenesis. American Society for Microbiology, Washington, D. C.1995Google Scholar). Furthermore, a of pol II-dependent also induces apoptosis L. B. Mol. 1997; PubMed Google Scholar). that pol II is for the transcription of transcription of genes not to to apoptosis induced by pol II inhibition or Although is that such cell death is by of the mechanism of apoptosis by transcriptional blockade unknown. We have now the mechanism of apoptosis that in response to transcriptional caused by of cells to RNA or to a high of UV Inhibition of transcription resulted in accumulation of p53 and cell death both in normal and in cells the induction of DNA damage. Although transcription of p53 target genes was as a of pol II the accumulation of p53 was for apoptosis. We also that a fraction of the accumulated p53 including on or to mitochondria. In that pol II inhibition induces the down-regulation of cyclin-dependent which is a target of allowing cells to S phase and to undergo apoptosis. Our the that blockage of pol II-dependent transcription transcription-independent apoptosis. and and and cells by B. and cells in with a cells used in the with α-amanitin or as and for p53 or a of p53 of was by the into into cells in as Y. T. C. M. T. S. H. H. Genes 9: PubMed Scopus Google Scholar). We used the target for pol II large subunit siRNA, The with with the of a used the to target the J. W. A. K. T. Nature. 2001; PubMed Scopus Google Scholar). UV with PBS, to UV radiation a of or and then in for the with for and UV by to with PBS, in and with PBS, for with A and with for was with a and data with of cells with BrdUrd, for with and with then for with a of a to with PI, and by of was by of the fraction of cells with a DNA as well as by of DNA with the of a cell death of cells in the of cells with for with a of the which a of in and for with with PI, and by of and used are in the and with TBS, for with with TBS, and with for then with the for to p53 to p53 to pol II and to with TBS, the cells with with PI, with and with a by of BrdUrd, cells with for for with with TBS, and with a to RNA was cells with the of and to with II reverse The phase of was to to to for by (pol II p21Cip1, Bax, or and of for for and for and was with a The by on used in the W. Google Scholar, Y. G. Y. Tanaka M. M. T. S. Res. 1995; PubMed Scopus Google Scholar). and encode p21Cip1, and the of the The was used as a and in the cell as H. N. Nakamura H. S. T. 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PubMed Scopus Google Scholar), cells with α-amanitin a in the of and to and H. shown in that of cells to α-amanitin resulted in a in the of the cell of p53 the of cells to death induced by that the apoptosis by pol II is used RNA interference to of the pol II large which is to pol II-dependent of cells with small interfering for the pol II large subunit resulted in in of the protein to the data by of pol II induced apoptosis in cells but not in cells α-amanitin induces cell death by activation of apoptotic that the of DNA with the data by α-amanitin induced a in the of DNA in cells in the of cells with also that α-amanitin induced a in the of cells with a of apoptosis. that cells are to apoptosis A and of p53 in cells to this of of but not that of the of cells to apoptosis and the that p53 is for this of In the apoptosis induced by α-amanitin was by the of the results that inhibition of pol II-dependent transcription and apoptosis. pol II and p53 DNA induces the ubiquitination of the of the of pol II A. Sharp P.A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) and consequent protein degradation S.J. M. C. O. Res. 1996; PubMed Scopus Google Scholar). We the of α-amanitin on the of the of pol II in or cells by and The induced degradation of pol II in both of that p53 not to pol II that apoptosis induced by α-amanitin was shown to the of the on the of with L. B. Mol. 1997; PubMed Google Scholar, M. Zhang Chen A.J. PubMed Scopus Google Scholar, M. T. 1994; 9: Google Scholar), that α-amanitin the accumulation of p53 in cells of p53 by inhibition of pol II was also by of pol II large subunit that the p53 accumulation by α-amanitin was not attributable to the induction of DNA damage, for the of the which a of DNA double-strand J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, C. C. J. Biol. PubMed Scopus Google Scholar), in cells by the of attributable to apoptotic DNA cells for the of to induced the formation of α-amanitin did p53 accumulation was this results that the accumulation of p53 induced by α-amanitin is not caused by the induction of The accumulation and activation of p53 are by including protein and W. Biol. 2003; PubMed Scopus Google Scholar). that of p53 contributes to both the and activation of the the of p53 on and in cells with or α-amanitin was as was p53 in the of of was not with the in the of this with that of in cells K. Arakawa H. Tanaka T. Matsuda K. Tanikawa C. Mori T. Nishimori H. Tamai K. Tokino T. Nakamura Y. Taya Y. Cell. 2000; 102: 849-862Abstract Full Text Full Text PDF PubMed Scopus (1031) Google Scholar). In in the of was with the of p53 accumulation, and was not in cells with results thus that α-amanitin a p53 response in to and a pathway that that for the p53 in response to DNA damage. of p53 Genes in pol II-dependent that p53-mediated apoptosis induced by α-amanitin is independent of the transactivation of the of the of p53 target including for p21Cip1, Bax, Jacks T. Vogelstein B. A.J. Cell. Full Text PDF PubMed Scopus Google Scholar), and S. Arakawa H. Tanaka T. H. Taya Y. M. Nakamura Y. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), in cells with or α-amanitin for the of the for p53 target genes α-amanitin did The of p53 was by of cells with α-amanitin but not by to that the of p53 target genes was not in cells the not data that transcriptional blockade a p53-dependent apoptosis that is not p53-mediated in of p53 to in have suggested that p53-dependent apoptosis in the of transcription (12Caelles C. Helmberg A. Karin M. Nature. 1994; 370: 220-223Crossref PubMed Scopus (843) Google Scholar, 13Haupt Y. Rowan S. Shaulian E. Vousden K.H. Oren M. Genes Dev. 1995; 9: 2170-2183Crossref PubMed Scopus (522) Google Scholar) and that a fraction of p53 molecules that accumulate in response to DNA damage translocates to mitochondria and apoptosis (14Marchenko N.D. Zaika A. Moll U.M. J. Biol. Chem. 2000; 275: 16202-16212Abstract Full Text Full Text PDF PubMed Scopus (790) Google Scholar, 15Mihara M. Erster S. Zaika A. Petrenko O. Chittenden T. Pancoska P. Moll U.M. Mol. Cell. 2003; 11: 577-590Abstract Full Text Full Text PDF PubMed Scopus (1496) Google Scholar). We therefore p53 molecules that accumulate in response to transcriptional blockade to mitochondria. was by normal that have cells are for the of p53 the cells have and large and We also that α-amanitin p53 accumulation and apoptosis in cells A and as in Although p53 protein was a in the of was in in cells and was to mitochondria in a of cells also that p53 accumulated by α-amanitin is in mitochondrial and mitochondrial p53 molecules are on thus that p53 molecules that accumulate in response to transcriptional blockade to the mitochondria, which the apoptotic and S the of the cell in S phase in a manner of pol II by also the of S phase cells in to to the of α-amanitin on cell cycle cells with α-amanitin or and then in the or of which induces cell cycle arrest in through activation of the with A. Mol. 2002; PubMed Scopus Google Scholar), of the cells with which is RNA polymerase or resulted in or In cells with α-amanitin and accumulated predominantly in the S phase in phase of or not to A and the retinoblastoma protein was in cells with was in cells as was in cells to a DNA polymerase which induced S phase Furthermore, the of a nuclear protein is during DNA arrest Y. T. C. M. T. S. H. H. Genes 9: PubMed Scopus Google Scholar), was not by of cells with was by with or that cells to α-amanitin progress through the and arrest in S We the mechanism by which cells are to S phase accumulation of DNA damage is to induce of the cyclin-dependent p53-dependent transactivation A. C. T. S. Kinzler K.W. Vogelstein B. Science. PubMed Scopus Google Scholar). to and the of both and the complexes of with A or of cells to S Genes Dev. PubMed Scopus Google Scholar). that the of protein and in both the cells and the pol cells and and cells to S phase despite p53 this in the of during cell cycle of the cells cells by and then into α-amanitin or the of which and induces The of the was and that of the was for cells with α-amanitin with the of cells with or that the of protein was in cells to was in response to The of is not by transcriptional induction but also by degradation J. G. M. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). the down-regulation of was attributable to protein degradation by the cells with α-amanitin in the of a The in the of induced by α-amanitin was by that in response to both transcriptional suppression and protein degradation to the accumulation of in cells and to S phase of the is a in the to phase C. P. PubMed Google Scholar). the mechanism of S phase arrest in the of in cells that was not in cells with that the cells are as a of down-regulation of this Apoptosis on into S that α-amanitin induced apoptosis the release of cells arrest a that with the We therefore cells with α-amanitin undergo apoptosis as S cells by and then to in the or of α-amanitin with α-amanitin a in through S phase with In with α-amanitin resulted in a large in the of cells for which a of and a of the the cells to accumulate in S phase Furthermore, this apoptotic was in the cells during S phase but not that α-amanitin induces p53-dependent apoptosis as cells S This is by the that cells in which p53 was to mitochondria BrdUrd, that S phase We the that induction of arrest is to apoptosis in The the cell cycle in phase by the of the both transcriptional and G. R. Res. 2000; PubMed Scopus (62) Google Scholar). the in the of the cell of the or also induced cell cycle arrest phase and apoptosis results that S phase is for the apoptosis induced by transcriptional of p53 and of to then down-regulation of is also for the induction of apoptosis by of cells with α-amanitin resulted in p53 accumulation and apoptosis This the that p53 accumulation induction the apoptosis. We thus this by of p53 in the and that this induces apoptosis α-amanitin Furthermore, a of p53-mediated transcriptional activation K. Science. PubMed Scopus Google Scholar), did not the induction of apoptosis in cells by of p53 that the transactivation of p53 not to this the that the p53-mediated apoptosis is by the accumulation of p53 that transcriptional blockade induces p53-mediated transcription-independent used cells a We established cells p53 or a of transactivation which is thus to C. M. E. L. PubMed Scopus Google Scholar). with α-amanitin induced apoptosis in cells not p53 but also in cells the cells to α-amanitin results thus that apoptosis induced by transcriptional blockade is p53-dependent but UV p53-mediated that inhibition of pol II by α-amanitin or resulted in the p53 accumulation to apoptosis. We to is this of cell (16Luo Z. Zheng J. Lu Y. Bregman D.B. Mutat. Res. 2001; 486: 259-274Crossref PubMed Scopus (62) Google Scholar), of cells to a high of UV radiation induced the degradation of pol II LS, resulting in transcriptional blockade and apoptosis the This induced p53 accumulation and down-regulation to of α-amanitin and pol II In the high p53 was predominantly in the mitochondrial fraction thus that accumulation of p53 in mitochondria with down-regulation of p21Cip1, which resulted transcriptional to apoptosis in high of pol II-dependent transcription has shown to trigger a cell death M. Zhang Chen A.J. PubMed Scopus Google Scholar). the mechanism that such apoptosis has remained Furthermore, recent have that p53 to the mitochondria and induce apoptosis in a manner (14Marchenko N.D. Zaika A. Moll U.M. J. Biol. Chem. 2000; 275: 16202-16212Abstract Full Text Full Text PDF PubMed Scopus (790) Google Scholar, 15Mihara M. Erster S. Zaika A. Petrenko O. Chittenden T. Pancoska P. Moll U.M. Mol. Cell. 2003; 11: 577-590Abstract Full Text Full Text PDF PubMed Scopus (1496) Google Scholar), but the this apoptosis have remained unclear. We now evidence that Inhibition of pol II by α-amanitin and high UV induces p53 accumulation induction of p21Cip1, of cells into S and p53-dependent but cell death by the translocation of p53 to mitochondria. Our data thus into the mechanism of cell death induced by transcriptional Inhibition of pol II by p53 and p53-dependent induced by α-amanitin was in in cells in the cells and was in the of a that transcriptional blockade induces apoptosis. Furthermore, this was by the that the cells apoptosis by of The accumulation of p53 to attributable to inhibition of p53 degradation, that the of p53 was by α-amanitin are with results T. 2002; Google Scholar), that the accumulation of p53 induced by inhibition of pol II-dependent transcription results down-regulation of in addition to the by of p53 protein to p53 In also that α-amanitin induces p53 The of which is by Prives C. Biol. 2000; PubMed Scopus Google Scholar), contributes to the and activation of the The induced the of p53 on which is by the ataxia S. L. S. Taya Y. L. Prives C. Y. Y. Y. Science. 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Biol. 1996; PubMed Scopus Google Scholar). that transcriptional by inhibition of pol II results in cell cycle arrest during DNA and induces apoptosis in S of p53 to and Apoptosis in S genes mediate p53-dependent cell death have p53 target genes encode proteins that to mitochondria and the mitochondrial membrane of mitochondrial apoptotic proteins Bax, PUMA, and We that the accumulation of p53 induced by α-amanitin did not in the transcriptional activation of of the p53 target genes Furthermore, the of and which are also H. A.J. R. Lowe S.W. Science. PubMed Scopus Google Scholar), was not by α-amanitin in cells thus that apoptosis induced by transcriptional blockade is by p53 in a transcription-independent that p53 is to the apoptotic pathways in the both death and A fraction of accumulated p53 molecules also translocates to the mitochondria and apoptosis in cells with DNA damage M. Erster S. Zaika A. Petrenko O. Chittenden T. Pancoska P. Moll U.M. Mol. Cell. 2003; 11: 577-590Abstract Full Text Full Text PDF PubMed Scopus (1496) Google Scholar). The p53 protein induces permeabilization of the outer mitochondrial membrane by complexes with the protective proteins Bcl-xL and Bcl-2, resulting in the release of cytochrome c into the It has also shown to and to induce the translocation of to mitochondria, resulting in cytochrome c release T. L. M. Science. PubMed Scopus Google Scholar). cellular that trigger the transcription-independent translocation of p53 to mitochondria We that transcriptional blockade induces p53 to mitochondria and that a of molecules also translocates to mitochondria in cells the p53 molecules that to mitochondria in cells on and and such translocation was in cells S on this that the p53 molecules that accumulate in response to transcriptional blockade trigger apoptosis by mitochondria. of p53-mediated Apoptosis by induction of DNA lesions by high doses of UV radiation results in the ubiquitination and degradation of pol II LS, transcriptional and recruitment of DNA repair proteins (16Luo Z. Zheng J. Lu Y. Bregman D.B. Mutat. Res. 2001; 486: 259-274Crossref PubMed Scopus (62) Google Scholar, 17Lee K.B. Wang D. Lippard S.J. Sharp P.A. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4239-4244Crossref PubMed Scopus (154) Google Scholar). inhibition of transcription as a of a failure to repair such DNA lesions results in cell death by apoptosis (18Friedberg E. Walker G. Siede W. DNA Repair and Mutagenesis. American Society for Microbiology, Washington, D. C.1995Google Scholar). that high UV radiation induced pol II degradation, p53 accumulation, down-regulation of and p53-dependent to the of α-amanitin UV was shown to induce transcription of the and to the of p53 with the of the resulting in repression of activation and cell death E. M. M. Karin M. Cell. 2000; Full Text Full Text PDF PubMed Google Scholar). in addition to the by transcriptional blockade the of DNA lesions to apoptosis by a p53-dependent It is to the apoptosis contributes to the p53-mediated cell cells with in the of the cell death was in to the p53-mediated is This that p53 accumulated by DNA damage apoptosis both and It has that of the agents such as cisplatin and the are to with transcription M. PubMed Scopus Google Scholar). translocation of p53 to mitochondria as a mechanism to apoptosis for cells transcription is by and DNA in the p53 thus both the transcription-dependent and apoptotic activities of p53 and to the of We R. Ohki for the of p53 and of of and and in for and to the with
Arima et al. (Tue,) studied this question.