This article was downloaded by: [Fondren Library, Rice University ] On: 15 April 2015, At: 10:21 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
Primary cilia and senescence: a sensitive issue a
a
Suchira Gallage & Jesús Gil a
Cell Proliferation Group; MRC Clinical Sciences Centre; Imperial College London; Hammersmith Campus; London, UK; Email: ; Published online: 30 Oct 2014.
Click for updates To cite this article: Suchira Gallage & Jesús Gil (2014) Primary cilia and senescence: a sensitive issue, Cell Cycle, 13:17, 2653-2654, DOI: 10.4161/15384101.2014.948785 To link to this article: http://dx.doi.org/10.4161/15384101.2014.948785
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, 2653--2654; September 1, 2014; © 2014 Taylor & Francis Group, LLC
Primary cilia and senescence: A sensitive issue Comment on: Breslin L, et al. Cell Cycle 2014; 13:2773–79; http://dx.doi.org/10.4161/15384101.2015.945868
Downloaded by [Fondren Library, Rice University ] at 10:21 15 April 2015
Suchira Gallage and Jes us Gil; Cell Proliferation Group; MRC Clinical Sciences Centre; Imperial College London; Hammersmith Campus; London, UK; Email: [email protected]; http://dx.doi.org/10.4161/15384101.2014.948785
Primary cilia (PC) are primordial, thin, hair-like organelles that protrude from the surface of vertebrate cells acting as a nexus that sense and transduce various extracellular signals, particularly that of Hedgehog (Hh) signaling.1 PC have been implicated in development and cancer as well as in a group of genetic disorders termed ciliopathies that affect a diverse range of organs in which the underlying phenomenon is structural or functional abnormalities of cilia.1 PC have a dual role in cancer as they promote or prevent tumor development depending on whether Hh signaling is activated at receptor level or downstream.2 Many tumor cells, such as those from pancreatic tumors, often lack cilia, highlighting that PC may be growth-inhibitory.3 However, the association depends on tumor type, as PC are present in human basal cell carcinomas (BCCs) as well as in distinct molecular subgroups of medulloblastomas.2 Uncontrolled cell proliferation is a hallmark of cancer. Therefore, senescence, a stable cell cycle arrest induced by replicative exhaustion or in response to stresses such as oncogene activation, is a potent barrier against tumorigenesis.4
The percentage of PC-containing cells increases in response to quiescence, a transient form of cell cycle arrest, but whether senescence promotes ciliogenesis and if so, what role PC plays in senescence remains to be addressed. The current manuscript by Morrison and colleagues5 shows that senescent (late passage) human fibroblasts display both increased frequency and length of PC, compared to proliferating (young passage) fibroblasts. Importantly, the expression of Hh signaling components were lower in fibroblasts undergoing replicative senescence in comparison to proliferating cells. Inhibition of Hh signaling decreased cell proliferation and extended the length of PC in proliferating young fibroblasts, suggesting that Hh signaling inhibits ciliogenesis and replicative senescence in human fibroblasts (Fig. 1). Additionally, promoting ciliogenesis by depleting CP110, a negative regulator of ciliogenesis, was sufficient to reduce the proliferative capacity of young cells. However, overexpressing CP110 failed to reinstitute the proliferation of senescent cells. These findings would fit with the growth-inhibitory functions of PC and would
suggest that the increase in PC observed in senescent cells could contribute to tumor suppression and that there is a need to suppress PC during cancer progression. However, as it seems to be the case with PC and tumorigenesis, the relation between PC and senescence is not clear-cut. It was previously reported that only a small percentage of primary human mammary epithelial cells (HMECs) exhibited PC and these PC-containing HMECs displayed low levels of p16INK4A, a marker of senescence.6 In addition, depletion of p16INK4A or increased Hh signaling via IHH promoted the formation of PC.6 In the same direction, cilia were absent both from pancreatic intraepithelial neoplasias (PanINs), which are preneoplastic lesions enriched in senescent cells, and in the resulting pancreatic ductal adenocarcinomas (PDACs).3 Therefore, an alternative explanation could be that loss of PC is a cancer-related phenotype that is acquired early in tumor progression (at the senescent stage), as it happens with global alterations in DNA methylation.
Figure 1. Relationship between senescence and the primary cilia. Frequency of primary cilia increases during senescence in human fibroblasts (middle) but not in human mammary epithelial cells (HMECs, right). During pancreatic tumorigenesis (left), primary cilia that are observed in normal ducts are lost in pancreatic intraepithelial neoplasias (PanIN) and pancreatic ductal adenocarcinomas (PDAC). PanIN lesions are enriched in senescent cells. www.landesbioscience.com
Cell Cycle
2653
Downloaded by [Fondren Library, Rice University ] at 10:21 15 April 2015
The differences observed between the two studies5,6 could be due to different gene expression patterns, ciliary signaling or the frequency of basal PC present in human senescing fibroblasts and HMECs, as Morrison and colleagues suggested.5 There are also molecular differences between replicative senescence in human fibroblasts and the M0-barrier observed in primary HMECs. Some similarities were also noted in the two reports, as mitogenesis was impaired by the inhibition of Hh signaling through the GLI2 transcription factor in both human fibroblasts and HMECs.5,6 More importantly, if conclusions are to be drawn on how the relation between
2654
senescence and ciliogenesis impacts cancer, the fate of PC needs to be studied in response to oncogene-induced senescence (OIS) and compared with the existing observations during replicative senescence. It is also tempting to speculate that primary cilia may play a role in developmental senescence,7 especially knowing the importance of these structures in transducing Hh signaling during vertebrate development. Importantly, as the list of roles that primary cilia play in physiology and pathology is ever growing, the finding that ciliogenesis increases in senescent cells may present a novel therapeutic target for cancer and ageing as well as help in understanding the molecular basis of ciliopathies.
Cell Cycle
1. 2. 3.
4.
5. 6. 7.
References Goetz SC, et al. Nat Rev Genet 2010; 11:331-44; PMID: 20395968; http://dx.doi.org/10.1038/nrg2774 ̊ Toftgard R. Nat Med 2009; 15:994-6; PMID: 19734870; http://dx.doi.org/10.1038/nm0909-994 Seeley ES, et al. Cancer Res 2009; 69:422-30; PMID: 19147554; http://dx.doi.org/10.1158/0008-5472. CAN-08-1290 Kuilman T, et al. Genes Dev 2010; 24:2463-79; PMID: 21078816; http://dx.doi.org/10.1101/gad. 1971610 Breslin L, et al. Cell Cycle 2014; 13:2773-79; http:// dx.doi.org/10.4161/15384101.2015.945868 Bishop CL, et al. Mol Cell 2010; 40:533-47; PMID: 21095584; http://dx.doi.org/10.1016/j.molcel.2010.10.027 Mu~ noz-Espin, et al. Nat Rev Mol Cel Biol 2014; 15:482-496; PMID: 24954210; http://dx.doi.org/ 10.1038/nrm3823.
Volume 13 Issue 17
Cell Cycle Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kccy20
Primary cilia and senescence: a sensitive issue a
a
Suchira Gallage & Jesús Gil a
Cell Proliferation Group; MRC Clinical Sciences Centre; Imperial College London; Hammersmith Campus; London, UK; Email: ; Published online: 30 Oct 2014.
Click for updates To cite this article: Suchira Gallage & Jesús Gil (2014) Primary cilia and senescence: a sensitive issue, Cell Cycle, 13:17, 2653-2654, DOI: 10.4161/15384101.2014.948785 To link to this article: http://dx.doi.org/10.4161/15384101.2014.948785
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, 2653--2654; September 1, 2014; © 2014 Taylor & Francis Group, LLC
Primary cilia and senescence: A sensitive issue Comment on: Breslin L, et al. Cell Cycle 2014; 13:2773–79; http://dx.doi.org/10.4161/15384101.2015.945868
Downloaded by [Fondren Library, Rice University ] at 10:21 15 April 2015
Suchira Gallage and Jes us Gil; Cell Proliferation Group; MRC Clinical Sciences Centre; Imperial College London; Hammersmith Campus; London, UK; Email: [email protected]; http://dx.doi.org/10.4161/15384101.2014.948785
Primary cilia (PC) are primordial, thin, hair-like organelles that protrude from the surface of vertebrate cells acting as a nexus that sense and transduce various extracellular signals, particularly that of Hedgehog (Hh) signaling.1 PC have been implicated in development and cancer as well as in a group of genetic disorders termed ciliopathies that affect a diverse range of organs in which the underlying phenomenon is structural or functional abnormalities of cilia.1 PC have a dual role in cancer as they promote or prevent tumor development depending on whether Hh signaling is activated at receptor level or downstream.2 Many tumor cells, such as those from pancreatic tumors, often lack cilia, highlighting that PC may be growth-inhibitory.3 However, the association depends on tumor type, as PC are present in human basal cell carcinomas (BCCs) as well as in distinct molecular subgroups of medulloblastomas.2 Uncontrolled cell proliferation is a hallmark of cancer. Therefore, senescence, a stable cell cycle arrest induced by replicative exhaustion or in response to stresses such as oncogene activation, is a potent barrier against tumorigenesis.4
The percentage of PC-containing cells increases in response to quiescence, a transient form of cell cycle arrest, but whether senescence promotes ciliogenesis and if so, what role PC plays in senescence remains to be addressed. The current manuscript by Morrison and colleagues5 shows that senescent (late passage) human fibroblasts display both increased frequency and length of PC, compared to proliferating (young passage) fibroblasts. Importantly, the expression of Hh signaling components were lower in fibroblasts undergoing replicative senescence in comparison to proliferating cells. Inhibition of Hh signaling decreased cell proliferation and extended the length of PC in proliferating young fibroblasts, suggesting that Hh signaling inhibits ciliogenesis and replicative senescence in human fibroblasts (Fig. 1). Additionally, promoting ciliogenesis by depleting CP110, a negative regulator of ciliogenesis, was sufficient to reduce the proliferative capacity of young cells. However, overexpressing CP110 failed to reinstitute the proliferation of senescent cells. These findings would fit with the growth-inhibitory functions of PC and would
suggest that the increase in PC observed in senescent cells could contribute to tumor suppression and that there is a need to suppress PC during cancer progression. However, as it seems to be the case with PC and tumorigenesis, the relation between PC and senescence is not clear-cut. It was previously reported that only a small percentage of primary human mammary epithelial cells (HMECs) exhibited PC and these PC-containing HMECs displayed low levels of p16INK4A, a marker of senescence.6 In addition, depletion of p16INK4A or increased Hh signaling via IHH promoted the formation of PC.6 In the same direction, cilia were absent both from pancreatic intraepithelial neoplasias (PanINs), which are preneoplastic lesions enriched in senescent cells, and in the resulting pancreatic ductal adenocarcinomas (PDACs).3 Therefore, an alternative explanation could be that loss of PC is a cancer-related phenotype that is acquired early in tumor progression (at the senescent stage), as it happens with global alterations in DNA methylation.
Figure 1. Relationship between senescence and the primary cilia. Frequency of primary cilia increases during senescence in human fibroblasts (middle) but not in human mammary epithelial cells (HMECs, right). During pancreatic tumorigenesis (left), primary cilia that are observed in normal ducts are lost in pancreatic intraepithelial neoplasias (PanIN) and pancreatic ductal adenocarcinomas (PDAC). PanIN lesions are enriched in senescent cells. www.landesbioscience.com
Cell Cycle
2653
Downloaded by [Fondren Library, Rice University ] at 10:21 15 April 2015
The differences observed between the two studies5,6 could be due to different gene expression patterns, ciliary signaling or the frequency of basal PC present in human senescing fibroblasts and HMECs, as Morrison and colleagues suggested.5 There are also molecular differences between replicative senescence in human fibroblasts and the M0-barrier observed in primary HMECs. Some similarities were also noted in the two reports, as mitogenesis was impaired by the inhibition of Hh signaling through the GLI2 transcription factor in both human fibroblasts and HMECs.5,6 More importantly, if conclusions are to be drawn on how the relation between
2654
senescence and ciliogenesis impacts cancer, the fate of PC needs to be studied in response to oncogene-induced senescence (OIS) and compared with the existing observations during replicative senescence. It is also tempting to speculate that primary cilia may play a role in developmental senescence,7 especially knowing the importance of these structures in transducing Hh signaling during vertebrate development. Importantly, as the list of roles that primary cilia play in physiology and pathology is ever growing, the finding that ciliogenesis increases in senescent cells may present a novel therapeutic target for cancer and ageing as well as help in understanding the molecular basis of ciliopathies.
Cell Cycle
1. 2. 3.
4.
5. 6. 7.
References Goetz SC, et al. Nat Rev Genet 2010; 11:331-44; PMID: 20395968; http://dx.doi.org/10.1038/nrg2774 ̊ Toftgard R. Nat Med 2009; 15:994-6; PMID: 19734870; http://dx.doi.org/10.1038/nm0909-994 Seeley ES, et al. Cancer Res 2009; 69:422-30; PMID: 19147554; http://dx.doi.org/10.1158/0008-5472. CAN-08-1290 Kuilman T, et al. Genes Dev 2010; 24:2463-79; PMID: 21078816; http://dx.doi.org/10.1101/gad. 1971610 Breslin L, et al. Cell Cycle 2014; 13:2773-79; http:// dx.doi.org/10.4161/15384101.2015.945868 Bishop CL, et al. Mol Cell 2010; 40:533-47; PMID: 21095584; http://dx.doi.org/10.1016/j.molcel.2010.10.027 Mu~ noz-Espin, et al. Nat Rev Mol Cel Biol 2014; 15:482-496; PMID: 24954210; http://dx.doi.org/ 10.1038/nrm3823.
Volume 13 Issue 17
