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Cell Cycle Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kccy20
Enter the nucleus to exit the cycle a
a
Lenno Krenning & René H Medema a
Division of Cell Biology I and Cancer Genomic Center; The Netherlands Cancer Institute; Amsterdam, The Netherlands; Email: Published online: 30 Oct 2014.
Click for updates To cite this article: Lenno Krenning & René H Medema (2014) Enter the nucleus to exit the cycle, Cell Cycle, 13:17, 2651-2652, DOI: 10.4161/15384101.2014.948783 To link to this article: http://dx.doi.org/10.4161/15384101.2014.948783
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
CELL CYCLE NEWS & VIEWS Cell Cycle 13:17, 2651--2652; September 1, 2014; © 2014 Taylor & Francis Group, LLC
Enter the nucleus to exit the cycle Comment on: M€ ullers E, et al. Cell Cycle 2014; 13:2733-43; http://dx.doi.org/10.4161/15384101.2015.945831
Downloaded by [New York University] at 21:17 08 January 2015
Lenno Krenning and Rene H Medema; Division of Cell Biology I and Cancer Genomic Center; The Netherlands Cancer Institute; Amsterdam, The Netherlands; Email: [email protected]; http://dx.doi.org/10.4161/15384101.2014.948783
The cellular response to DNA damage nuclear Cyclin B1 fail to induce mitosis upon addition, M€ ullers et al. now report that transranges from transient cell cycle arrest to the inhibition of the DNA damage checkpoint2,4 formed U2OS cells, unlike non-transformed induction of apoptosis or senescence. It is (Fig. 1, top). The finding that Cyclin B1 cells, do not translocate Cyclin B1 to the generally thought that permanent cell cycle becomes nuclear in response to DNA damage nucleus in response to DNA damage.4 withdrawal is initiated in response to severe, is counterintuitive, since nuclear translocation Accordingly, these cells maintain recovery irreparable DNA damage. This way, cells can of Cyclin B1 marks the onset of mitosis in an competence much longer than do non-transprevent the propagation of a damaged unperturbed cell cycle. However, it was shown formed cells (Fig. 1, middle). genome. Alternatively, following DNA repair, that, following DNA damage, the p21-bound Induction of DNA damage, through irradiathe cell can shut down the checkpoint and Cyclin B1-Cdk1 complexes in the nucleus are tion or exposure to DNA damaging cheresume the cell cycle, a process known as inactive and cannot be dephosphorylated by motherapeutics, is routinely used in the checkpoint recovery. If a DNA damaged- Cdc25.1,2 Consequently, nuclear p21-bound treatment of cancer. This strategy relies induced arrest is established in G2 phase, cells Cyclin B1-Cdk1 complexes are refractory to on the induction of cell death or cell cycle exit need to maintain the expression of cell cycle reactivation upon silencing of the DNA dam- in the damaged cells. However, resistance to regulatory proteins, such as Cyclin B1, in order age checkpoint, thus marking a point-of-no- these therapies may arise over time due to to retain the ability to resume cell cycle return during the DNA damage response. In the survival of a few cells. Given the findings progression. On the other hand, degradation of cell cycle regulatory proteins due to the activation of APC/CCdh1 leads to cell cycle exit. In this edition of Cell Cycle M€ ullers et al. have investigated the regulation of checkpoint recovery and cell cycle exit, by investigating Cyclin B1 dynamics in response to DNA damage in single cells. Consistent with previous observations,1–3 M€ ullers et al. find that non-transformed cells respond to DNA damage by translocating Cyclin B1 to the nucleus in a p53- and p21-dependent manner.4 Nuclear translocation of Cyclin B1 is followed by APC/CCdh1 dependent degradation of Cyclin B1. Interestingly, DNA damageinduced nuclear translocation of Cyclin B1 marks Figure 1. DNA damage in p53-proficient cells induces nuclear translocation of Cyclin B1 and subsequent APC/CCdh1 activation, leading to cell cycle exit (top). p53-impaired cells fail to translocate Cyclin B1, and maintain a reversible checkpoint the point-of-no-return (middle). Forced p21-expression or Wip1 inhibition following DNA damage may result in nuclear translocation of Cyclin during the DNA damage B1 and induction of cell cycle exit in p53-impaired cells (bottom). response, as cells with www.landesbioscience.com
Cell Cycle
2651
fact that Cyclin B1 does not translocate to the nucleus in these cells after DNA damage. Similar mutations were found in cancer patients, highlighting the clinical relevance of these findings. The recent discovery of a Wip1 inhibitor7 makes it possible to investigate whether inhibition of Wip1 in U2OS and other Wip1mutated cells can reactivate a DNA damageinduced cell cycle exit mechanism (Fig. 1, bottom), and possibly improve therapeutic outcome in patients.
1.
References Charrier-Savournin FB, et al. Mol Biol Cell 2004; 15:3965-76; PMID:15181148; http://dx.doi.org/ 10.1091/mbc.E03-12-0871
2.
3.
4. 5.
6.
7.
Krenning L, et al. Mol Cell 2014; 55:59-72; PMID:24910099; http://dx.doi.org/10.1016/j.molcel. 2014.05.007 Johmura Y, et al. Mol Cell 2014; 55:73-84; PMID:24910096; http://dx.doi.org/10.1016/j.molcel. 2014.05.003 M€ ullers E, et al. Cell Cycle 2014; 13:2733-43; http:// dx.doi.org/10.4161/15384101.2015.945831 Smits VA, et al. J Biol Chem 2000; 275:30638-43; PMID:10913154; http://dx.doi.org/10.1074/jbc.M005 437200 Kleiblova P, et al. J Cell Biol 2013; 201:511-21; PMID:23649806; http://dx.doi.org/10.1083/jcb.201210 031 Gilmartin AG, et al. Nat Chem Biol 2014; 10:181-7; PMID:24390428; http://dx.doi.org/10.1038/nchembio. 1427
Downloaded by [New York University] at 21:17 08 January 2015
from M€ ullers et al, it will be interesting to see if restoration of the cell-cycle exit machinery in these transformed cells can increase sensitivity to DNA damaging agents and potentially decrease therapy resistance. In support of this hypothesis is the finding that forced induction of p21 in U2OS cells can result in the nuclear translocation of inactive Cyclin B1,5 indicating that the underlying cell-cycle exit mechanisms are present yet suppressed in these cells (Fig. 1, bottom). Recently described gain-offunction mutations of Wip1 in U2OS and HCT116 cells were shown to contribute to the suppression of p21-induction upon DNA damage,6 providing a possible explanation for the
2652
Cell Cycle
Volume 13 Issue 17
Cell Cycle Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kccy20
Enter the nucleus to exit the cycle a
a
Lenno Krenning & René H Medema a
Division of Cell Biology I and Cancer Genomic Center; The Netherlands Cancer Institute; Amsterdam, The Netherlands; Email: Published online: 30 Oct 2014.
Click for updates To cite this article: Lenno Krenning & René H Medema (2014) Enter the nucleus to exit the cycle, Cell Cycle, 13:17, 2651-2652, DOI: 10.4161/15384101.2014.948783 To link to this article: http://dx.doi.org/10.4161/15384101.2014.948783
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
CELL CYCLE NEWS & VIEWS Cell Cycle 13:17, 2651--2652; September 1, 2014; © 2014 Taylor & Francis Group, LLC
Enter the nucleus to exit the cycle Comment on: M€ ullers E, et al. Cell Cycle 2014; 13:2733-43; http://dx.doi.org/10.4161/15384101.2015.945831
Downloaded by [New York University] at 21:17 08 January 2015
Lenno Krenning and Rene H Medema; Division of Cell Biology I and Cancer Genomic Center; The Netherlands Cancer Institute; Amsterdam, The Netherlands; Email: [email protected]; http://dx.doi.org/10.4161/15384101.2014.948783
The cellular response to DNA damage nuclear Cyclin B1 fail to induce mitosis upon addition, M€ ullers et al. now report that transranges from transient cell cycle arrest to the inhibition of the DNA damage checkpoint2,4 formed U2OS cells, unlike non-transformed induction of apoptosis or senescence. It is (Fig. 1, top). The finding that Cyclin B1 cells, do not translocate Cyclin B1 to the generally thought that permanent cell cycle becomes nuclear in response to DNA damage nucleus in response to DNA damage.4 withdrawal is initiated in response to severe, is counterintuitive, since nuclear translocation Accordingly, these cells maintain recovery irreparable DNA damage. This way, cells can of Cyclin B1 marks the onset of mitosis in an competence much longer than do non-transprevent the propagation of a damaged unperturbed cell cycle. However, it was shown formed cells (Fig. 1, middle). genome. Alternatively, following DNA repair, that, following DNA damage, the p21-bound Induction of DNA damage, through irradiathe cell can shut down the checkpoint and Cyclin B1-Cdk1 complexes in the nucleus are tion or exposure to DNA damaging cheresume the cell cycle, a process known as inactive and cannot be dephosphorylated by motherapeutics, is routinely used in the checkpoint recovery. If a DNA damaged- Cdc25.1,2 Consequently, nuclear p21-bound treatment of cancer. This strategy relies induced arrest is established in G2 phase, cells Cyclin B1-Cdk1 complexes are refractory to on the induction of cell death or cell cycle exit need to maintain the expression of cell cycle reactivation upon silencing of the DNA dam- in the damaged cells. However, resistance to regulatory proteins, such as Cyclin B1, in order age checkpoint, thus marking a point-of-no- these therapies may arise over time due to to retain the ability to resume cell cycle return during the DNA damage response. In the survival of a few cells. Given the findings progression. On the other hand, degradation of cell cycle regulatory proteins due to the activation of APC/CCdh1 leads to cell cycle exit. In this edition of Cell Cycle M€ ullers et al. have investigated the regulation of checkpoint recovery and cell cycle exit, by investigating Cyclin B1 dynamics in response to DNA damage in single cells. Consistent with previous observations,1–3 M€ ullers et al. find that non-transformed cells respond to DNA damage by translocating Cyclin B1 to the nucleus in a p53- and p21-dependent manner.4 Nuclear translocation of Cyclin B1 is followed by APC/CCdh1 dependent degradation of Cyclin B1. Interestingly, DNA damageinduced nuclear translocation of Cyclin B1 marks Figure 1. DNA damage in p53-proficient cells induces nuclear translocation of Cyclin B1 and subsequent APC/CCdh1 activation, leading to cell cycle exit (top). p53-impaired cells fail to translocate Cyclin B1, and maintain a reversible checkpoint the point-of-no-return (middle). Forced p21-expression or Wip1 inhibition following DNA damage may result in nuclear translocation of Cyclin during the DNA damage B1 and induction of cell cycle exit in p53-impaired cells (bottom). response, as cells with www.landesbioscience.com
Cell Cycle
2651
fact that Cyclin B1 does not translocate to the nucleus in these cells after DNA damage. Similar mutations were found in cancer patients, highlighting the clinical relevance of these findings. The recent discovery of a Wip1 inhibitor7 makes it possible to investigate whether inhibition of Wip1 in U2OS and other Wip1mutated cells can reactivate a DNA damageinduced cell cycle exit mechanism (Fig. 1, bottom), and possibly improve therapeutic outcome in patients.
1.
References Charrier-Savournin FB, et al. Mol Biol Cell 2004; 15:3965-76; PMID:15181148; http://dx.doi.org/ 10.1091/mbc.E03-12-0871
2.
3.
4. 5.
6.
7.
Krenning L, et al. Mol Cell 2014; 55:59-72; PMID:24910099; http://dx.doi.org/10.1016/j.molcel. 2014.05.007 Johmura Y, et al. Mol Cell 2014; 55:73-84; PMID:24910096; http://dx.doi.org/10.1016/j.molcel. 2014.05.003 M€ ullers E, et al. Cell Cycle 2014; 13:2733-43; http:// dx.doi.org/10.4161/15384101.2015.945831 Smits VA, et al. J Biol Chem 2000; 275:30638-43; PMID:10913154; http://dx.doi.org/10.1074/jbc.M005 437200 Kleiblova P, et al. J Cell Biol 2013; 201:511-21; PMID:23649806; http://dx.doi.org/10.1083/jcb.201210 031 Gilmartin AG, et al. Nat Chem Biol 2014; 10:181-7; PMID:24390428; http://dx.doi.org/10.1038/nchembio. 1427
Downloaded by [New York University] at 21:17 08 January 2015
from M€ ullers et al, it will be interesting to see if restoration of the cell-cycle exit machinery in these transformed cells can increase sensitivity to DNA damaging agents and potentially decrease therapy resistance. In support of this hypothesis is the finding that forced induction of p21 in U2OS cells can result in the nuclear translocation of inactive Cyclin B1,5 indicating that the underlying cell-cycle exit mechanisms are present yet suppressed in these cells (Fig. 1, bottom). Recently described gain-offunction mutations of Wip1 in U2OS and HCT116 cells were shown to contribute to the suppression of p21-induction upon DNA damage,6 providing a possible explanation for the
2652
Cell Cycle
Volume 13 Issue 17
