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Cell Cycle Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kccy20
Molecular mechanisms orchestrating cyclin stability a
ab
Yongxing Gong & Timothy A Chan a
Human Oncology and Pathogenesis Program; Memorial Sloan Kettering Cancer Center; New York, NY USA b
Department of Radiation Oncology; Memorial Sloan Kettering Cancer Center; New York, NY USA Published online: 30 Oct 2014.
Click for updates To cite this article: Yongxing Gong & Timothy A Chan (2014) Molecular mechanisms orchestrating cyclin stability, Cell Cycle, 13:16, 2487-2488, DOI: 10.4161/15384101.2014.946376 To link to this article: http://dx.doi.org/10.4161/15384101.2014.946376
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
EDITORIALS: CELL CYCLE FEATURES Cell Cycle 13:16, 2487--2488; August 15, 2014; © 2014 Taylor & Francis Group, LLC
Molecular mechanisms orchestrating cyclin stability Yongxing Gong1 and Timothy A Chan1,2,* Human Oncology and Pathogenesis Program; Memorial Sloan Kettering Cancer Center; New York, NY USA; 2Department of Radiation Oncology; Memorial Sloan Kettering Cancer Center; New York, NY USA
Downloaded by [Michigan State University] at 11:07 15 January 2015
1
A fundamental abnormality in cancer is the unchecked proliferation of cells. Rather than responding appropriately to signals that control normal cell division, cancer cells grow and divide in an uncontrolled manner, invade normal tissues and organs, and eventually spread throughout the body. We have shown that PARK2 is a critical regulator of the core cell cycle machinery that controls cell proliferation. PARK2, a gene on chromosome 6q25.2q27 originally discovered as a frequent cause of autosomal recessive juvenile parkinsonism (ARJP), has previously been identified as a tumor suppressor gene by our lab.1 Recently, through genetic analysis of approximately 5,000 tumors samples across 11 tumor types, we found that PARK2 undergoes copy number loss in about 30% of tumors, with deletions occurring most often in serous ovarian, breast, colon, and bladder carcinomas. Intriguingly, PARK2 genetic loss was mutually exclusive with amplification of the genes encoding cyclin D1 (CCND1), cyclin E1 (CCNE1), and CDK4, suggesting that PARK2 and these cell cycle machinery components interact in a common pathway.2 Aside from these results, our study dramatically demonstrates the power of in silico pan-cancer genetic analysis for elucidating novel biology. PARK2 functions as an E3 ligase for ubiquitin-mediated proteolysis.3 Our experiments demonstrated that PARK2 depletion leads to abnormal accumulation of all cyclin D and E isoforms.2 Furthermore, cancer-related mutations of PARK2 abrogated its activity to regulate cyclin D and E stability. PARK2 degradation of cyclin D occurred through proteasomemediated ubiquitination, and this process
was dependent on phosphorylation of cyclin D1 at threonine 286. Strikingly, using pulse-chase experiments, we showed that PARK2 was necessary and sufficient to dictate cyclin D half-life even in the presence of other Fbox proteins that have been proposed to target cyclin D. The elucidation of the core cell cycle machinery and how this machinery is regulated has spanned more than 3 decades. One of the most challenging efforts has been to understand the mechanisms governing cyclin stability and coordination of stability across related cyclin classes. Proper targeting of cyclins for degradation is required for normal cell cycle control. This is performed by a number of ubiquitin E3 ligases. The Skp/Cullin/Fbox complexes (SCF) regulate progression through G1 and entry into S phase by degrading G1 cyclin-dependent kinase inhibitors (CKIs) and G1 cyclins.4 A few candidate E3 ligases have been suggested to target G1 cyclins for proteolysis. For example, FBX4 (which is a component of the SCFFBX4/aB-crystallin complex) targets and ubiquitinates cyclin D, whereas cyclin E ubiquitination is directed by the SCFFBW7 complex.5,6 Prior to our work, the mechanisms underlying the orchestration of different types of cyclins were unknown. Our work showed that PARK2 targets both cyclins D and E to regulate their stability. We discovered that PARK2 is a component of a new class of novel SCF-like ubiquitin complexes, PCF4 and PCF7, which regulate the degradation of cyclins D and E respectively. PARK2 binds to its substrate cyclin D and other PCF4 members (Cullin-1, aB-crystallin, and FBX4). Similarly, PARK binds to FBXW7 and
Cullin, forming the PCF7 complex, which targets cyclin E for destruction. Interestingly, we found that PARK2 and FBX4 act in a synergistic manner to target cyclin D1. When both PARK2 and FBX4 are inactivated, cyclin D accumulation is dramatically greater than would be predicted by a simple additive model. And, combining recombinant PARK2 with FBX4 in vitro synergistically enhances overall E3 ligase activity. Accordingly, a recent report suggested that SCFFBX4 alone is not sufficient to control cyclin D1 stability.7 Our study shows that PARK2 is a master orchestrator of G1/S cyclin stability. PARK2 functions as a component of E3 ubiquitin ligase complexes that drive cyclin D and E degradation. This model is supported by a convergence of data from pan-cancer genetic analysis, functional genomic analysis, and biochemical dissection (Fig. 1). It would seem that PARK2 functions in a manner analogous to that of the cyclin dependent kinase inhibitor CDKN2A (p16). Whereas p16 controls the activity of the G1/S cyclins by binding and inhibiting the enzymatic activities of cyclin/CDK complexes, PARK2 inhibits G1/S progression by acting at the level of cyclin stability. These findings answer long-sought questions about how coordination of cyclin levels occurs but open up many new questions. How is PARK2 enzymatic activity post-translationally regulated? What is the biochemical mechanism of synergy between PARK2 and FBX4? How does CDKN2A and PARK2 work together to regulate G1/S progression? And, how do we exploit PARK2 deficiency in cancer therapy? Future studies will be needed to answer these important questions.
*Correspondence to: Timothy A Chan; Email: [email protected] Submitted: 07/02/2014; Accepted: 07/16/2014 http://dx.doi.org/10.4161/15384101.2014.946376
www.landesbioscience.com
Cell Cycle
2487
Downloaded by [Michigan State University] at 11:07 15 January 2015
Figure 1. PARK2 inactivation and cell cycle dysfunction. PARK2 helps control levels of cyclin D and E by targeting them for degradation. In cancer cells that have lost PARK2, cyclin D and E accumulate, leading to increased phosphorylation of Rb and cell cycle progression.
References 1. 2. 3.
Veeriah S, et al. Nat Genet 2010; 42:77-82; PMID:19946270; http://dx.doi.org/10.1038/ng.491 Yongxing G, et al. Nat Genet 2014; 46:588-94; http:// dx.doi.org/10.1038/ng.2981 Shimura H, et al. Nat Genet 2000; 25:302-5; PMID:10888878; http://dx.doi.org/10.1038/77060
2488
4. 5.
Frescas D, et al. Nat Rev Cancer 2008; 8:438-49; PMID:18500245; http://dx.doi.org/10.1038/nrc2396 Lin DI, et al. Mol Cell 2006; 24:355-66; PMID:17081987; http://dx.doi.org/10.1016/j.molcel. 2006.09.007
Cell Cycle
6. 7.
Strohmaier H, et al. Nature 2001; 413:316-22; PMID:11565034; http://dx.doi.org/10.1038/35095076 Kanie T, et al. Mol Cell Biol 2012; 32:590-605; PMID:22124152; http://dx.doi.org/10.1128/MCB. 06570-11
Volume 13 Issue 16
Cell Cycle Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kccy20
Molecular mechanisms orchestrating cyclin stability a
ab
Yongxing Gong & Timothy A Chan a
Human Oncology and Pathogenesis Program; Memorial Sloan Kettering Cancer Center; New York, NY USA b
Department of Radiation Oncology; Memorial Sloan Kettering Cancer Center; New York, NY USA Published online: 30 Oct 2014.
Click for updates To cite this article: Yongxing Gong & Timothy A Chan (2014) Molecular mechanisms orchestrating cyclin stability, Cell Cycle, 13:16, 2487-2488, DOI: 10.4161/15384101.2014.946376 To link to this article: http://dx.doi.org/10.4161/15384101.2014.946376
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
EDITORIALS: CELL CYCLE FEATURES Cell Cycle 13:16, 2487--2488; August 15, 2014; © 2014 Taylor & Francis Group, LLC
Molecular mechanisms orchestrating cyclin stability Yongxing Gong1 and Timothy A Chan1,2,* Human Oncology and Pathogenesis Program; Memorial Sloan Kettering Cancer Center; New York, NY USA; 2Department of Radiation Oncology; Memorial Sloan Kettering Cancer Center; New York, NY USA
Downloaded by [Michigan State University] at 11:07 15 January 2015
1
A fundamental abnormality in cancer is the unchecked proliferation of cells. Rather than responding appropriately to signals that control normal cell division, cancer cells grow and divide in an uncontrolled manner, invade normal tissues and organs, and eventually spread throughout the body. We have shown that PARK2 is a critical regulator of the core cell cycle machinery that controls cell proliferation. PARK2, a gene on chromosome 6q25.2q27 originally discovered as a frequent cause of autosomal recessive juvenile parkinsonism (ARJP), has previously been identified as a tumor suppressor gene by our lab.1 Recently, through genetic analysis of approximately 5,000 tumors samples across 11 tumor types, we found that PARK2 undergoes copy number loss in about 30% of tumors, with deletions occurring most often in serous ovarian, breast, colon, and bladder carcinomas. Intriguingly, PARK2 genetic loss was mutually exclusive with amplification of the genes encoding cyclin D1 (CCND1), cyclin E1 (CCNE1), and CDK4, suggesting that PARK2 and these cell cycle machinery components interact in a common pathway.2 Aside from these results, our study dramatically demonstrates the power of in silico pan-cancer genetic analysis for elucidating novel biology. PARK2 functions as an E3 ligase for ubiquitin-mediated proteolysis.3 Our experiments demonstrated that PARK2 depletion leads to abnormal accumulation of all cyclin D and E isoforms.2 Furthermore, cancer-related mutations of PARK2 abrogated its activity to regulate cyclin D and E stability. PARK2 degradation of cyclin D occurred through proteasomemediated ubiquitination, and this process
was dependent on phosphorylation of cyclin D1 at threonine 286. Strikingly, using pulse-chase experiments, we showed that PARK2 was necessary and sufficient to dictate cyclin D half-life even in the presence of other Fbox proteins that have been proposed to target cyclin D. The elucidation of the core cell cycle machinery and how this machinery is regulated has spanned more than 3 decades. One of the most challenging efforts has been to understand the mechanisms governing cyclin stability and coordination of stability across related cyclin classes. Proper targeting of cyclins for degradation is required for normal cell cycle control. This is performed by a number of ubiquitin E3 ligases. The Skp/Cullin/Fbox complexes (SCF) regulate progression through G1 and entry into S phase by degrading G1 cyclin-dependent kinase inhibitors (CKIs) and G1 cyclins.4 A few candidate E3 ligases have been suggested to target G1 cyclins for proteolysis. For example, FBX4 (which is a component of the SCFFBX4/aB-crystallin complex) targets and ubiquitinates cyclin D, whereas cyclin E ubiquitination is directed by the SCFFBW7 complex.5,6 Prior to our work, the mechanisms underlying the orchestration of different types of cyclins were unknown. Our work showed that PARK2 targets both cyclins D and E to regulate their stability. We discovered that PARK2 is a component of a new class of novel SCF-like ubiquitin complexes, PCF4 and PCF7, which regulate the degradation of cyclins D and E respectively. PARK2 binds to its substrate cyclin D and other PCF4 members (Cullin-1, aB-crystallin, and FBX4). Similarly, PARK binds to FBXW7 and
Cullin, forming the PCF7 complex, which targets cyclin E for destruction. Interestingly, we found that PARK2 and FBX4 act in a synergistic manner to target cyclin D1. When both PARK2 and FBX4 are inactivated, cyclin D accumulation is dramatically greater than would be predicted by a simple additive model. And, combining recombinant PARK2 with FBX4 in vitro synergistically enhances overall E3 ligase activity. Accordingly, a recent report suggested that SCFFBX4 alone is not sufficient to control cyclin D1 stability.7 Our study shows that PARK2 is a master orchestrator of G1/S cyclin stability. PARK2 functions as a component of E3 ubiquitin ligase complexes that drive cyclin D and E degradation. This model is supported by a convergence of data from pan-cancer genetic analysis, functional genomic analysis, and biochemical dissection (Fig. 1). It would seem that PARK2 functions in a manner analogous to that of the cyclin dependent kinase inhibitor CDKN2A (p16). Whereas p16 controls the activity of the G1/S cyclins by binding and inhibiting the enzymatic activities of cyclin/CDK complexes, PARK2 inhibits G1/S progression by acting at the level of cyclin stability. These findings answer long-sought questions about how coordination of cyclin levels occurs but open up many new questions. How is PARK2 enzymatic activity post-translationally regulated? What is the biochemical mechanism of synergy between PARK2 and FBX4? How does CDKN2A and PARK2 work together to regulate G1/S progression? And, how do we exploit PARK2 deficiency in cancer therapy? Future studies will be needed to answer these important questions.
*Correspondence to: Timothy A Chan; Email: [email protected] Submitted: 07/02/2014; Accepted: 07/16/2014 http://dx.doi.org/10.4161/15384101.2014.946376
www.landesbioscience.com
Cell Cycle
2487
Downloaded by [Michigan State University] at 11:07 15 January 2015
Figure 1. PARK2 inactivation and cell cycle dysfunction. PARK2 helps control levels of cyclin D and E by targeting them for degradation. In cancer cells that have lost PARK2, cyclin D and E accumulate, leading to increased phosphorylation of Rb and cell cycle progression.
References 1. 2. 3.
Veeriah S, et al. Nat Genet 2010; 42:77-82; PMID:19946270; http://dx.doi.org/10.1038/ng.491 Yongxing G, et al. Nat Genet 2014; 46:588-94; http:// dx.doi.org/10.1038/ng.2981 Shimura H, et al. Nat Genet 2000; 25:302-5; PMID:10888878; http://dx.doi.org/10.1038/77060
2488
4. 5.
Frescas D, et al. Nat Rev Cancer 2008; 8:438-49; PMID:18500245; http://dx.doi.org/10.1038/nrc2396 Lin DI, et al. Mol Cell 2006; 24:355-66; PMID:17081987; http://dx.doi.org/10.1016/j.molcel. 2006.09.007
Cell Cycle
6. 7.
Strohmaier H, et al. Nature 2001; 413:316-22; PMID:11565034; http://dx.doi.org/10.1038/35095076 Kanie T, et al. Mol Cell Biol 2012; 32:590-605; PMID:22124152; http://dx.doi.org/10.1128/MCB. 06570-11
Volume 13 Issue 16
