This article was downloaded by: [Michigan State University] On: 16 February 2015, At: 01:35 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Cell Cycle Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kccy20
NIAM’s tangled web of growth control a
a
Ian Love & Steven Grossman a
Division of Hematology, Oncology, and Palliative Care and Massey Cancer Center; Virginia Commonwealth University; Richmond, VA USA Published online: 08 May 2014.
Click for updates To cite this article: Ian Love & Steven Grossman (2014) NIAM’s tangled web of growth control, Cell Cycle, 13:11, 1660-1660, DOI: 10.4161/cc.29150 To link to this article: http://dx.doi.org/10.4161/cc.29150
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. 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. Versions of published Taylor & Francis and Routledge Open articles and Taylor & Francis and Routledge Open Select articles posted to institutional or subject repositories or any other third-party website are without warranty from Taylor & Francis of any kind, either expressed or implied, including, but not limited to, warranties of merchantability, fitness for a particular purpose, or non-infringement. Any opinions and views expressed in this article 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 & 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. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions It is essential that you check the license status of any given Open and Open Select article to confirm conditions of access and use.
Cell Cycle News & & Views Cell Cycle News Views
Cell Cycle 13:11, 1660–1660; June 1, 2014; © 2014 Landes Bioscience
NIAM’s tangled web of growth control Comment on: Reed SM, et al. Cell Cycle 2014; 13:1288–98; PMID:24621507; http://dx.doi.org/10.4161/cc.28202
Downloaded by [Michigan State University] at 01:35 16 February 2015
Ian M Love and Steven R Grossman*; Division of Hematology, Oncology, and Palliative Care and Massey Cancer Center; Virginia Commonwealth University; Richmond, VA USA; http://dx.doi.org/10.4161/cc.29150; *Correspondence to: [email protected]
Aside from its canonical activity activating p53 in response to oncogene activation, the tumor suppressor (alternate reading frame) ARF exhibits p53-independent antiproliferative and tumor-suppressive activities. In search of the mechanism underpinning these activities, a number of ARF-interacting proteins have been identified in the years since the ARF/MDM2 interaction was characterized as the means by which ARF activates p53. These novel ARF interactors include ARFbinding protein1 (ARF-BP1), nucleophosmin, C-terminal binding protein (CtBP)-family corepressors, and the nuclear interactor of ARF and MDM2 (NIAM).1 Of these known ARF interactors, NIAM is unique in its action as a putative tumor suppressor and suppressor of cell growth, rather than an oncogene or growth/ survival factor that is antagonized by ARF. In the April 15, 2014 issue of Cell Cycle, Reed et al.2 investigated the pathways downstream of NIAM required for its growth-suppressive properties. What little was previously known about NIAM strongly suggested its ability to induce cell cycle arrest channels through multiple parallel pathways. 3 NIAM promotes both ARF-dependent and -independent activation of p53 transcriptional activity and is downregulated in a number of pancreatic adenocarcinoma cell lines and human tumors. Mysteriously, however, NIAM also promotes cell cycle arrest through a p53-independent pathway. These observations suggest an unusually complex interplay among NIAM, ARF, p53, and the cell cycle-regulatory machinery. Reed et al. attempt to elucidate the mechanisms underlying NIAM’s control of the p53-dependent arm of its cell cycle-inhibitory activities, discovering that physiologic levels of NIAM are necessary for full p53 transactivation of the p21 promoter, and that NIAM promotes acetylation of lysine 120 of p53, a
1660
modification regarded as critical for activation of the apoptotic arm of the p53 transcription program.4,5 The authors further demonstrate that p53 activation by NIAM occurs through 2 distinct pathways: disruption of the p53– MDM2 complex, and association of NIAM with the Tip60 acetyltransferase. In a surprising twist, the authors show that depletion of Tip60 only partially reverses NIAM-mediated K120 acetylation, and that an N-terminal NIAM truncation mutant, competent for MDM2 binding, Tip60 binding, chromatin association, and cell cycle arrest, is unable to drive K120 acetylation of p53. While it is possible that residual Tip60 or the presence of hMOF is sufficient for acetylation of a limited pool of p53, the inability of the truncation mutant to promote p53 acetylation despite retaining robust Tip60 interaction is surprising and may suggest that the NIAM C terminus recruits additional functions necessary for in vivo acetylation of p53 at sites of p53-dependent transcription. The data are also a clear indication that the K120 acetylation driven by NIAM is dispensable for its broader functions in inhibiting MDM2–p53 interaction and promoting cell cycle arrest. Together, Reed et al.’s data support a model whereby one pool of NIAM sequesters MDM2 from p53 and allows p53 activation, while another pool promotes activation and association with the p53 acetylase and coactivator Tip60. However, advances in our understanding often raise as many questions as they provide answers, and regulation of proliferation by NIAM is no exception. For example, if K120 acetylation by NIAM is separable from Tip60 binding and p53 activation, how is NIAM regulating Tip60 function? It is possible that Tip60 in this model functions as a canonical histone acetyltransferase, acetylating histones in the vicinity of p53 target promoters, and that NIAM facilitates this activity through
Cell Cycle
enhancing DNA binding of Tip60, or modulating its interaction with negative regulators. Interestingly, Tip60 is known to interact with MDM2 and negatively regulate MDM2mediated NEDDylation,6 while NIAM interacts with both of these factors but, notably, not p53. It is also interesting to note that the NIAM N terminus encodes all functions necessary for p53-dependent growth arrest, including binding of Tip60 and MDM2, while the C terminus, upon which K120 acetylation is dependent, seems to provide some function necessary to direct the acetylase activity of Tip60 toward p53. Future work will be instrumental in determining whether NIAM regulation of p53 activities occurs through regulation of a Tip60–MDM2 interaction. Of broader interest will be the exploration of NIAM’s role in tumorigenesis—its downregulation suggests that NIAM activity may be selected against during tumorigenesis, so it will be critical to develop animal models to probe NIAM function and to carefully analyze the wealth of available high-throughput sequence and microarray data to determine whether NIAM functions as a tumor suppressor in certain tumors, perhaps in a mutually exclusive fashion with Tip60 and p53.
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3.
4.
5.
6.
References Sherr CJ. Nat Rev Cancer 2006; 6:663-73; PMID:16915296; http://dx.doi.org/10.1038/nrc1954 Reed SM, et al. Cell Cycle 2014; 13:1288-98; PMID:24621507; http://dx.doi.org/10.4161/ cc.28202 Tompkins VS, et al. J Biol Chem 2007; 282:132233; PMID:17110379; http://dx.doi.org/10.1074/jbc. M609612200 Tang Y, et al. Mol Cell 2006; 24:827-39; PMID:17189186; http://dx.doi.org/10.1016/j. molcel.2006.11.021 Sykes SM, et al. Mol Cell 2006; 24:841-51; PMID:17189187; http://dx.doi.org/10.1016/j. molcel.2006.11.026 Dohmesen C, et al. Cell Cycle 2008; 7:222-31; PMID:18264029; http://dx.doi.org/10.4161/ cc.7.2.5185
Volume 13 Issue 11
Cell Cycle Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kccy20
NIAM’s tangled web of growth control a
a
Ian Love & Steven Grossman a
Division of Hematology, Oncology, and Palliative Care and Massey Cancer Center; Virginia Commonwealth University; Richmond, VA USA Published online: 08 May 2014.
Click for updates To cite this article: Ian Love & Steven Grossman (2014) NIAM’s tangled web of growth control, Cell Cycle, 13:11, 1660-1660, DOI: 10.4161/cc.29150 To link to this article: http://dx.doi.org/10.4161/cc.29150
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. 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. Versions of published Taylor & Francis and Routledge Open articles and Taylor & Francis and Routledge Open Select articles posted to institutional or subject repositories or any other third-party website are without warranty from Taylor & Francis of any kind, either expressed or implied, including, but not limited to, warranties of merchantability, fitness for a particular purpose, or non-infringement. Any opinions and views expressed in this article 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 & 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. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions It is essential that you check the license status of any given Open and Open Select article to confirm conditions of access and use.
Cell Cycle News & & Views Cell Cycle News Views
Cell Cycle 13:11, 1660–1660; June 1, 2014; © 2014 Landes Bioscience
NIAM’s tangled web of growth control Comment on: Reed SM, et al. Cell Cycle 2014; 13:1288–98; PMID:24621507; http://dx.doi.org/10.4161/cc.28202
Downloaded by [Michigan State University] at 01:35 16 February 2015
Ian M Love and Steven R Grossman*; Division of Hematology, Oncology, and Palliative Care and Massey Cancer Center; Virginia Commonwealth University; Richmond, VA USA; http://dx.doi.org/10.4161/cc.29150; *Correspondence to: [email protected]
Aside from its canonical activity activating p53 in response to oncogene activation, the tumor suppressor (alternate reading frame) ARF exhibits p53-independent antiproliferative and tumor-suppressive activities. In search of the mechanism underpinning these activities, a number of ARF-interacting proteins have been identified in the years since the ARF/MDM2 interaction was characterized as the means by which ARF activates p53. These novel ARF interactors include ARFbinding protein1 (ARF-BP1), nucleophosmin, C-terminal binding protein (CtBP)-family corepressors, and the nuclear interactor of ARF and MDM2 (NIAM).1 Of these known ARF interactors, NIAM is unique in its action as a putative tumor suppressor and suppressor of cell growth, rather than an oncogene or growth/ survival factor that is antagonized by ARF. In the April 15, 2014 issue of Cell Cycle, Reed et al.2 investigated the pathways downstream of NIAM required for its growth-suppressive properties. What little was previously known about NIAM strongly suggested its ability to induce cell cycle arrest channels through multiple parallel pathways. 3 NIAM promotes both ARF-dependent and -independent activation of p53 transcriptional activity and is downregulated in a number of pancreatic adenocarcinoma cell lines and human tumors. Mysteriously, however, NIAM also promotes cell cycle arrest through a p53-independent pathway. These observations suggest an unusually complex interplay among NIAM, ARF, p53, and the cell cycle-regulatory machinery. Reed et al. attempt to elucidate the mechanisms underlying NIAM’s control of the p53-dependent arm of its cell cycle-inhibitory activities, discovering that physiologic levels of NIAM are necessary for full p53 transactivation of the p21 promoter, and that NIAM promotes acetylation of lysine 120 of p53, a
1660
modification regarded as critical for activation of the apoptotic arm of the p53 transcription program.4,5 The authors further demonstrate that p53 activation by NIAM occurs through 2 distinct pathways: disruption of the p53– MDM2 complex, and association of NIAM with the Tip60 acetyltransferase. In a surprising twist, the authors show that depletion of Tip60 only partially reverses NIAM-mediated K120 acetylation, and that an N-terminal NIAM truncation mutant, competent for MDM2 binding, Tip60 binding, chromatin association, and cell cycle arrest, is unable to drive K120 acetylation of p53. While it is possible that residual Tip60 or the presence of hMOF is sufficient for acetylation of a limited pool of p53, the inability of the truncation mutant to promote p53 acetylation despite retaining robust Tip60 interaction is surprising and may suggest that the NIAM C terminus recruits additional functions necessary for in vivo acetylation of p53 at sites of p53-dependent transcription. The data are also a clear indication that the K120 acetylation driven by NIAM is dispensable for its broader functions in inhibiting MDM2–p53 interaction and promoting cell cycle arrest. Together, Reed et al.’s data support a model whereby one pool of NIAM sequesters MDM2 from p53 and allows p53 activation, while another pool promotes activation and association with the p53 acetylase and coactivator Tip60. However, advances in our understanding often raise as many questions as they provide answers, and regulation of proliferation by NIAM is no exception. For example, if K120 acetylation by NIAM is separable from Tip60 binding and p53 activation, how is NIAM regulating Tip60 function? It is possible that Tip60 in this model functions as a canonical histone acetyltransferase, acetylating histones in the vicinity of p53 target promoters, and that NIAM facilitates this activity through
Cell Cycle
enhancing DNA binding of Tip60, or modulating its interaction with negative regulators. Interestingly, Tip60 is known to interact with MDM2 and negatively regulate MDM2mediated NEDDylation,6 while NIAM interacts with both of these factors but, notably, not p53. It is also interesting to note that the NIAM N terminus encodes all functions necessary for p53-dependent growth arrest, including binding of Tip60 and MDM2, while the C terminus, upon which K120 acetylation is dependent, seems to provide some function necessary to direct the acetylase activity of Tip60 toward p53. Future work will be instrumental in determining whether NIAM regulation of p53 activities occurs through regulation of a Tip60–MDM2 interaction. Of broader interest will be the exploration of NIAM’s role in tumorigenesis—its downregulation suggests that NIAM activity may be selected against during tumorigenesis, so it will be critical to develop animal models to probe NIAM function and to carefully analyze the wealth of available high-throughput sequence and microarray data to determine whether NIAM functions as a tumor suppressor in certain tumors, perhaps in a mutually exclusive fashion with Tip60 and p53.
1. 2.
3.
4.
5.
6.
References Sherr CJ. Nat Rev Cancer 2006; 6:663-73; PMID:16915296; http://dx.doi.org/10.1038/nrc1954 Reed SM, et al. Cell Cycle 2014; 13:1288-98; PMID:24621507; http://dx.doi.org/10.4161/ cc.28202 Tompkins VS, et al. J Biol Chem 2007; 282:132233; PMID:17110379; http://dx.doi.org/10.1074/jbc. M609612200 Tang Y, et al. Mol Cell 2006; 24:827-39; PMID:17189186; http://dx.doi.org/10.1016/j. molcel.2006.11.021 Sykes SM, et al. Mol Cell 2006; 24:841-51; PMID:17189187; http://dx.doi.org/10.1016/j. molcel.2006.11.026 Dohmesen C, et al. Cell Cycle 2008; 7:222-31; PMID:18264029; http://dx.doi.org/10.4161/ cc.7.2.5185
Volume 13 Issue 11
