- Email: [email protected]
p27Kip1 and stathmin share the stage for the first time
Update
346
TRENDS in Cell Biology
Vol.15 No.7 July 2005
p27Kip1 and stathmin share the stage for the first time Camelia Iancu-Rubin and George F. Atweh Division of Hematology/Oncology, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA
Cell migration is essential for development, morphogenesis, tissue repair and tumor metastasis. p27Kip1 and stathmin are two cell-cycle-regulatory proteins that were recently shown to play important roles in the regulation of cell migration. In this article, we discuss a new study that places p27Kip1 and stathmin in the same pathway by showing that stathmin, a microtubuleregulatory protein, mediates the effects of p27Kip1 on cell motility. These findings provide new insights into migration and metastasis of tumor cells and the relationship of these processes to cell proliferation.
Introduction The process of tumor metastasis requires proliferation of tumor cells, separation from adjacent cells, migration through vascular or lymphatic channels, invasion of distant tissues and attraction of endothelial cells for tumor angiogenesis. The significance of metastasis to cancer pathology is underscored by the fact that more cancer patients die from metastasis than from primary tumors. A recent report by Baldassarre et al. sheds new light on the process of migration of tumor cells and its relationship to the cell cycle [1]. The studies suggest that stathmin, a well-known microtubule-regulatory protein, acts as the mediator of the effects of p27Kip1 on cell motility. p27Kip1 and stathmin play a role in cell migration p27Kip1 was discovered as an inhibitor of cyclin-dependent kinase (CDK) complexes in TGFb-arrested cells, and is a member of the Cip/Kip family of cyclin-dependent kinase inhibitors (CKIs). CKIs associate with a broad spectrum of cyclin–CDK complexes to negatively regulate progression through the G1 phase of the cell cycle. More recently, cytoplasmic p27Kip1 was shown to play a role in the regulation of cell migration [2]. p27Kip1 stimulated the migration of hepatocellular carcinoma cells and mouse embryonic fibroblasts [3,4]. These studies demonstrated that p27Kip1 can induce rearrangements of the actin cytoskeleton, either in a Rac-dependent manner [3] or through inhibition of RhoA activation [4]. By contrast, other studies showed that p27Kip1 inhibits the migration of endothelial cells and vascular smooth muscle cells [5,6]. Although all these studies suggest that p27Kip1 plays a role in cell migration, it is not clear whether the discrepancy between these reports (i.e. whether p27Kip1 inhibits or promotes cell migration) might be a reflection of Corresponding author: Atweh, G.F. ([email protected]). Available online 13 June 2005 www.sciencedirect.com
differences in the activity of cytoplasmic p27Kip1 in different cell types and/or of differences in the migration assays that were used. Stathmin is a cytosolic phosphoprotein that plays an important role in regulating microtubule dynamics in both interphase and mitosis [7]. Microtubules are major components of the cytoskeleton that are crucial for maintenance of cell shape, intracellular transport, cell motility and cell division. Microtubules consist of a–b-tubulin heteropolymers that continuously switch between phases of polymerization and depolymerization, a property known as dynamic instability [8]. The transition from a phase of growth to a phase of shrinkage is called ‘catastrophe’, while the transition from a phase of shrinkage to a phase of growth is called ‘rescue’. Microtubule dynamics are regulated by several families of proteins, including microtubule-associated proteins (MAPs) and microtubule-destabilizing proteins. Stathmin is a major microtubule-destabilizing protein that promotes microtubule depolymerization by two distinct mechanisms [9]. The first is a catastrophe-promoting microtubuledepolymerization activity that is necessary for the regulation of the mitotic spindle. The second is a tubulin-sequestering activity that inhibits microtubule polymerization and is necessary for the regulation of microtubule dynamics during interphase. Both activities are regulated by phosphorylation, which inactivates stathmin and prevents its binding to tubulin. Although stathmin can induce microtubule depolymerization in interphase, the functions mediated by its interphase activity are not well understood. Sobel and coworkers provided the first evidence that stathmin plays a role in cell motility by showing that inhibition of stathmin expression in Drosophila impairs germ cell migration [10]. Since then, two other studies have shown that stathmin is necessary for the migration of neurons in vivo and in vitro. Jin et al. demonstrated that antisense oligonucleotides that target stathmin mRNA inhibit migration of newly formed neurons of the olfactory system in adult rat brain [11]. Similarly, Giampietro et al. showed that migration of immortalized neurons is decreased when stathmin expression is downregulated and is increased when stathmin is overexpressed [12]. p27Kip1 regulates migration by a direct effect on stathmin Recently, Baldassarre and colleagues demonstrated that p27Kip1 expression inhibits the migration of HT-1080 fibrosarcoma cells and normal mouse fibroblasts. The authors were able to localize the migration-inhibitory
Update
TRENDS in Cell Biology
activity of p27Kip1 to the C-terminal 28 amino acids of the protein. Based on this, they hypothesized that the C-terminal domain might bind to interacting protein(s) that are important in the regulation of cell motility. Using a yeast two-hybrid assay, the authors identified stathmin as a partner protein that binds to p27Kip1 and demonstrated by co-immunoprecipitation in vivo interactions between p27Kip1 and stathmin in HT-1080 sarcoma cells, pork brain, mouse fetal brain and normal mouse fibroblasts adherent to fibronectin. Using an in vitro tubulin polymerization assay, Baldassarre et al. also showed that p27Kip1 interferes with the ability of stathmin to sequester tubulin, leading to increased microtubule polymerization. They next asked whether the interaction between p27Kip1 and stathmin is important for cell motility. Stathmin overexpression increased the migration of sarcoma cells, whereas stathmin inhibition decreased their migration. Moreover, stathmin-null mouse embryo fibroblasts (MEFs) showed migration defects that could be rescued by transfection of stathmin cDNA. Intriguingly, inhibition of migration of sarcoma cells by p27Kip1 overexpression was essentially neutralized by co-transfection with stathmin. Baldassarre and colleagues also showed that stathmin does not increase the migration of p27Kip1null MEFs, and p27Kip1 does not inhibit the migration of stathmin-null MEFs. Furthermore, they showed that a low p27Kip1/stathmin ratio in primary and metastatic sarcomas in vivo correlates with increased metastasis, suggesting that p27Kip1 might counteract the positive effect of stathmin on migration and metastasis. Although p27Kip1 and stathmin were originally discovered as important regulators of the eukaryotic cell cycle, both are now suggested to be involved in the process of cell migration. A dual role for stathmin in the regulation of cell proliferation and cell migration should not be surprising as microtubules are known to be important in both processes. The connection between the roles of p27Kip1 in cell proliferation and cell migration is not as obvious since these two functions of p27Kip1 are localized in different parts of the molecule and are exerted in different cellular compartments. The effects of p27Kip1 on cell motility were previously shown to be mediated through changes in the activities of Rho GTPases, which are important regulators of the actin cytoskeleton. The report of Baldassarre et al. provides the first indication that p27Kip1 regulates migration by a direct effect on stathmin, a known regulator of the microtubule cytoskeleton. p27Kip1 and stathmin: new questions As with all important new observations, those of Baldassarre et al. raise several new questions. Perhaps the most important of these relate to the stoichiometry of binding of p27Kip1 to stathmin in vivo. It is not clear whether the intracellular concentrations of the two molecules are compatible with the hypothesis that p27Kip1 inactivates stathmin by direct binding. As stathmin is expressed at very high levels in cancer cells, it is important to determine whether the intracellular concentrations of p27Kip1 are high enough to inhibit stathmin function by direct binding. The presence of a www.sciencedirect.com
Vol.15 No.7 July 2005
347
CDK inhibitor at a very high concentration in the nucleus would probably be incompatible with proliferation. However, high concentrations of p27Kip1 might be tolerated in the cytoplasm, where stathmin is localized. Another question raised by this report is whether p27Kip1 and stathmin could also interact indirectly to regulate cell motility. Figure 1 illustrates four possible interactions between p27Kip1 and stathmin. The first is a direct interaction that represents the binding of p27Kip1 to stathmin, as suggested by Baldassarre and colleagues [1]. The second is an indirect interaction between p27Kip1 and stathmin through the Rho GTPase pathway. Rac was previously shown to stabilize microtubules by phosphorylation-dependent inactivation of stathmin [13]. More recently, phosphorylation-dependent inactivation of stathmin, believed to be mediated by Rac, was shown to occur at the leading edge of motile A6 Xenopus cells [14]. Interestingly, the stimulatory effects of p27Kip1 on cell migration also appear to require the activation of Rac [3]. Thus, p27Kip1 might regulate cell migration by activating Rac, which can promote phosphorylation of stathmin and lead to microtubule stabilization. In a third possible interaction, p27Kip1 might modulate stathmin activity indirectly through its inhibitory effects on cyclin–CDK complexes. As stathmin is a substrate for CDK1, inhibition of CDK1 by p27Kip1 might prevent the inactivation of stathmin and lead to destabilization of microtubules. Alternatively, the inhibition of cyclin–CDK complexes by p27Kip1 might regulate stathmin function by a different mechanism. Because E2F transcription factors
p27 (ii)
Rac
(iii)
(iv)
(i)
CDKs
hKIS
E2F Stathmin
Microtubules
Migration
Proliferation
TRENDS in Cell Biology
Figure 1. Potential interactions between p27Kip1 and stathmin in the regulation of cell motility. Stathmin regulates microtubule dynamics during cell proliferation and cell migration. Changes in the expression and/or phosphorylation of stathmin could result in changes in microtubule stability, which lead to either inhibition or stimulation of cell motility. p27Kip1 has the potential for modulating stathmin expression and/or function through at least four different mechanisms: (i) p27Kip1 might directly interact with stathmin and prevent its microtubule-destabilizing activity [1]; (ii) p27Kip1 activates Rac [3], which can promote the phosphorylation of stathmin and inhibit its microtubule-destabilizing activity [14]; (iii) the inhibitory effect of p27Kip1 on cyclin-dependent kinases (CDKs) might result in either E2Fmediated downregulation of stathmin expression [15] or increased stathmin activity by means of CDK1 inactivation; (iv) p27Kip1 and stathmin might interact through the human kinase interacting stathmin (hKIS) that phosphorylates p27Kip1 and induces its translocation to the cytoplasm where stathmin is localized.
348
Update
TRENDS in Cell Biology
are known to activate the stathmin promoter [15], inhibition of the CDK–Rb–E2F pathway by p27Kip1 might result in decreased stathmin expression and lead to microtubule stabilization. Finally, a fourth way in which p27Kip1 and stathmin might interact is through the human kinase interacting stathmin (hKIS). This kinase was first discovered as a stathmin partner protein and later shown to phosphorylate stathmin. Interestingly, KIS was recently shown to phosphorylate p27Kip1 and promote its translocation from the nucleus to the cytoplasm, where it has to be to regulate the activity of stathmin.
Concluding remarks The description of a role for the physical interaction between p27Kip1 and stathmin in the regulation of cell motility is an important discovery that requires confirmation by other investigators. This discovery should encourage the investigation of other ways in which these two molecules might interact to regulate cell motility and possibly the cell cycle. It should be emphasized that all the indirect interactions that we described above are purely speculative and none has been verified experimentally. Nonetheless, the studies of Baldassarre and colleagues have already introduced a provocative new twist in our understanding of the regulation of cell motility and have brought together two players that had not shared the same stage before.
Vol.15 No.7 July 2005
References 1 Baldassarre, G. et al. (2005) p27Kip1-stathmin interaction influences sarcoma cell migration and invasion. Cancer Cell 7, 51–63 2 Denicourt, C. and Dowdy, S.F. (2004) Cip/Kip proteins: more than just CDKs inhibitors. Genes Dev. 18, 851–855 3 McAllister, S.S. et al. (2003) Novel p27Kip1 C-terminal scatter domain mediates Rac-dependent cell migration independent of cell cycle arrest functions. Mol. Cell. Biol. 23, 216–228 4 Besson, A. et al. (2004) p27Kip1 modulates cell migration through the regulation of RhoA activation. Genes Dev. 18, 862–876 5 Goukassian, D. et al. (2001) Overexpression of p27Kip1 by doxycyclineregulated adenoviral vectors inhibits endothelial cell proliferation and migration and impairs angiogenesis. FASEB J. 15, 1877–1885 6 Sun, J. et al. (2001) Role for p27Kip1 in vascular smooth muscle cell migration. Circulation 103, 2967–2972 7 Rubin, C.I. and Atweh, G.F. (2004) The role of stathmin in the regulation of the cell cycle. J. Cell. Biochem. 93, 242–250 8 Desai, A. and Mitchison, T.J. (1997) Microtubule polymerization dynamics. Annu. Rev. Cell Dev. Biol. 13, 83–117 9 Howell, B. et al. (1999) Dissociation of the tubulin-sequestering and microtubule catastrophe-promoting activities of oncoprotein 18/stathmin. Mol. Biol. Cell 10, 105–118 10 Ozon, S. et al. (2002) Drosophila stathmin: a microtubule-destabilizing factor involved in nervous system formation. Mol. Biol. Cell 13, 698–710 11 Jin, K. et al. (2004) Proteomic and immunochemical characterization of a role for stathmin in adult neurogenesis. FASEB J. 18, 287–299 12 Giampietro, C. et al. (2005) Stathmin expression modulates migratory properties of GN-11 neurons in vitro. Endocrinology 146, 1825–1834 13 Wittmann, T. et al. (2004) Regulation of microtubule destabilizing activity of Op18/stathmin downstream of Rac1. J. Biol. Chem. 279, 6196–6203 14 Niethammer, P. et al. (2004) Stathmin-tubulin interaction gradients in motile and mitotic cells. Science 303, 1862–1866 15 Polzin, R.G. et al. (2004) E2F sites in the Op18 promoter are required for high level of expression in the human prostate carcinoma cell line PC-3-M. Gene 341, 209–218
Acknowledgements We apologize to the authors whose studies were not cited because of space limitation.
0962-8924/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tcb.2005.05.008
Elsevier celebrates two anniversaries with gift to university libraries in the developing world In 1580, the Elzevir family began their printing and bookselling business in the Netherlands, publishing works by scholars such as John Locke, Galileo Galilei and Hugo Grotius. On 4 March 1880, Jacobus George Robbers founded the modern Elsevier company intending, just like the original Elzevir family, to reproduce fine editions of literary classics for the edification of others who shared his passion, other ’Elzevirians’. Robbers co-opted the Elzevir family’s old printer’s mark, visually stamping the new Elsevier products with a classic old symbol of the symbiotic relationship between publisher and scholar. Elsevier has since become a leader in the dissemination of scientific, technical and medical (STM) information, building a reputation for excellence in publishing, new product innovation and commitment to its STM communities. In celebration of the House of Elzevir’s 425th anniversary and the 125th anniversary of the modern Elsevier company, Elsevier will donate books to 10 university libraries in the developing world. Entitled ‘A Book in Your Name’, each of the 6 700 Elsevier employees worldwide has been invited to select one of the chosen libraries to receive a book donated by Elsevier. The core gift collection contains the company’s most important and widely used STM publications including Gray’s Anatomy, Dorland’s Illustrated Medical Dictionary, Essential Medical Physiology, Cecil Essentials of Medicine, Mosby’s Medical, Nursing and Allied Health Dictionary, The Vaccine Book, Fundamentals of Neuroscience, and Myles Textbook for Midwives. The 10 beneficiary libraries are located in Africa, South America and Asia. They include the Library of the Sciences of the University of Sierra Leone; the library of the Muhimbili University College of Health Sciences of the University of Dar es Salaam, Tanzania; the library of the College of Medicine of the University of Malawi; and the libraries of the University of Zambia, Universite du Mali, Universidade Eduardo Mondlane, Mozambique; Makerere University, Uganda; Universidad San Francisco de Quito, Ecuador; Universidad Francisco Marroquin, Guatemala; and the National Centre for Scientific and Technological Information (NACESTI), Vietnam. Through ‘A Book in Your Name’, the 10 libraries will receive approximately 700 books at a retail value of approximately 1 million US dollars.
For more information, visit www.elsevier.com www.sciencedirect.com
346
TRENDS in Cell Biology
Vol.15 No.7 July 2005
p27Kip1 and stathmin share the stage for the first time Camelia Iancu-Rubin and George F. Atweh Division of Hematology/Oncology, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA
Cell migration is essential for development, morphogenesis, tissue repair and tumor metastasis. p27Kip1 and stathmin are two cell-cycle-regulatory proteins that were recently shown to play important roles in the regulation of cell migration. In this article, we discuss a new study that places p27Kip1 and stathmin in the same pathway by showing that stathmin, a microtubuleregulatory protein, mediates the effects of p27Kip1 on cell motility. These findings provide new insights into migration and metastasis of tumor cells and the relationship of these processes to cell proliferation.
Introduction The process of tumor metastasis requires proliferation of tumor cells, separation from adjacent cells, migration through vascular or lymphatic channels, invasion of distant tissues and attraction of endothelial cells for tumor angiogenesis. The significance of metastasis to cancer pathology is underscored by the fact that more cancer patients die from metastasis than from primary tumors. A recent report by Baldassarre et al. sheds new light on the process of migration of tumor cells and its relationship to the cell cycle [1]. The studies suggest that stathmin, a well-known microtubule-regulatory protein, acts as the mediator of the effects of p27Kip1 on cell motility. p27Kip1 and stathmin play a role in cell migration p27Kip1 was discovered as an inhibitor of cyclin-dependent kinase (CDK) complexes in TGFb-arrested cells, and is a member of the Cip/Kip family of cyclin-dependent kinase inhibitors (CKIs). CKIs associate with a broad spectrum of cyclin–CDK complexes to negatively regulate progression through the G1 phase of the cell cycle. More recently, cytoplasmic p27Kip1 was shown to play a role in the regulation of cell migration [2]. p27Kip1 stimulated the migration of hepatocellular carcinoma cells and mouse embryonic fibroblasts [3,4]. These studies demonstrated that p27Kip1 can induce rearrangements of the actin cytoskeleton, either in a Rac-dependent manner [3] or through inhibition of RhoA activation [4]. By contrast, other studies showed that p27Kip1 inhibits the migration of endothelial cells and vascular smooth muscle cells [5,6]. Although all these studies suggest that p27Kip1 plays a role in cell migration, it is not clear whether the discrepancy between these reports (i.e. whether p27Kip1 inhibits or promotes cell migration) might be a reflection of Corresponding author: Atweh, G.F. ([email protected]). Available online 13 June 2005 www.sciencedirect.com
differences in the activity of cytoplasmic p27Kip1 in different cell types and/or of differences in the migration assays that were used. Stathmin is a cytosolic phosphoprotein that plays an important role in regulating microtubule dynamics in both interphase and mitosis [7]. Microtubules are major components of the cytoskeleton that are crucial for maintenance of cell shape, intracellular transport, cell motility and cell division. Microtubules consist of a–b-tubulin heteropolymers that continuously switch between phases of polymerization and depolymerization, a property known as dynamic instability [8]. The transition from a phase of growth to a phase of shrinkage is called ‘catastrophe’, while the transition from a phase of shrinkage to a phase of growth is called ‘rescue’. Microtubule dynamics are regulated by several families of proteins, including microtubule-associated proteins (MAPs) and microtubule-destabilizing proteins. Stathmin is a major microtubule-destabilizing protein that promotes microtubule depolymerization by two distinct mechanisms [9]. The first is a catastrophe-promoting microtubuledepolymerization activity that is necessary for the regulation of the mitotic spindle. The second is a tubulin-sequestering activity that inhibits microtubule polymerization and is necessary for the regulation of microtubule dynamics during interphase. Both activities are regulated by phosphorylation, which inactivates stathmin and prevents its binding to tubulin. Although stathmin can induce microtubule depolymerization in interphase, the functions mediated by its interphase activity are not well understood. Sobel and coworkers provided the first evidence that stathmin plays a role in cell motility by showing that inhibition of stathmin expression in Drosophila impairs germ cell migration [10]. Since then, two other studies have shown that stathmin is necessary for the migration of neurons in vivo and in vitro. Jin et al. demonstrated that antisense oligonucleotides that target stathmin mRNA inhibit migration of newly formed neurons of the olfactory system in adult rat brain [11]. Similarly, Giampietro et al. showed that migration of immortalized neurons is decreased when stathmin expression is downregulated and is increased when stathmin is overexpressed [12]. p27Kip1 regulates migration by a direct effect on stathmin Recently, Baldassarre and colleagues demonstrated that p27Kip1 expression inhibits the migration of HT-1080 fibrosarcoma cells and normal mouse fibroblasts. The authors were able to localize the migration-inhibitory
Update
TRENDS in Cell Biology
activity of p27Kip1 to the C-terminal 28 amino acids of the protein. Based on this, they hypothesized that the C-terminal domain might bind to interacting protein(s) that are important in the regulation of cell motility. Using a yeast two-hybrid assay, the authors identified stathmin as a partner protein that binds to p27Kip1 and demonstrated by co-immunoprecipitation in vivo interactions between p27Kip1 and stathmin in HT-1080 sarcoma cells, pork brain, mouse fetal brain and normal mouse fibroblasts adherent to fibronectin. Using an in vitro tubulin polymerization assay, Baldassarre et al. also showed that p27Kip1 interferes with the ability of stathmin to sequester tubulin, leading to increased microtubule polymerization. They next asked whether the interaction between p27Kip1 and stathmin is important for cell motility. Stathmin overexpression increased the migration of sarcoma cells, whereas stathmin inhibition decreased their migration. Moreover, stathmin-null mouse embryo fibroblasts (MEFs) showed migration defects that could be rescued by transfection of stathmin cDNA. Intriguingly, inhibition of migration of sarcoma cells by p27Kip1 overexpression was essentially neutralized by co-transfection with stathmin. Baldassarre and colleagues also showed that stathmin does not increase the migration of p27Kip1null MEFs, and p27Kip1 does not inhibit the migration of stathmin-null MEFs. Furthermore, they showed that a low p27Kip1/stathmin ratio in primary and metastatic sarcomas in vivo correlates with increased metastasis, suggesting that p27Kip1 might counteract the positive effect of stathmin on migration and metastasis. Although p27Kip1 and stathmin were originally discovered as important regulators of the eukaryotic cell cycle, both are now suggested to be involved in the process of cell migration. A dual role for stathmin in the regulation of cell proliferation and cell migration should not be surprising as microtubules are known to be important in both processes. The connection between the roles of p27Kip1 in cell proliferation and cell migration is not as obvious since these two functions of p27Kip1 are localized in different parts of the molecule and are exerted in different cellular compartments. The effects of p27Kip1 on cell motility were previously shown to be mediated through changes in the activities of Rho GTPases, which are important regulators of the actin cytoskeleton. The report of Baldassarre et al. provides the first indication that p27Kip1 regulates migration by a direct effect on stathmin, a known regulator of the microtubule cytoskeleton. p27Kip1 and stathmin: new questions As with all important new observations, those of Baldassarre et al. raise several new questions. Perhaps the most important of these relate to the stoichiometry of binding of p27Kip1 to stathmin in vivo. It is not clear whether the intracellular concentrations of the two molecules are compatible with the hypothesis that p27Kip1 inactivates stathmin by direct binding. As stathmin is expressed at very high levels in cancer cells, it is important to determine whether the intracellular concentrations of p27Kip1 are high enough to inhibit stathmin function by direct binding. The presence of a www.sciencedirect.com
Vol.15 No.7 July 2005
347
CDK inhibitor at a very high concentration in the nucleus would probably be incompatible with proliferation. However, high concentrations of p27Kip1 might be tolerated in the cytoplasm, where stathmin is localized. Another question raised by this report is whether p27Kip1 and stathmin could also interact indirectly to regulate cell motility. Figure 1 illustrates four possible interactions between p27Kip1 and stathmin. The first is a direct interaction that represents the binding of p27Kip1 to stathmin, as suggested by Baldassarre and colleagues [1]. The second is an indirect interaction between p27Kip1 and stathmin through the Rho GTPase pathway. Rac was previously shown to stabilize microtubules by phosphorylation-dependent inactivation of stathmin [13]. More recently, phosphorylation-dependent inactivation of stathmin, believed to be mediated by Rac, was shown to occur at the leading edge of motile A6 Xenopus cells [14]. Interestingly, the stimulatory effects of p27Kip1 on cell migration also appear to require the activation of Rac [3]. Thus, p27Kip1 might regulate cell migration by activating Rac, which can promote phosphorylation of stathmin and lead to microtubule stabilization. In a third possible interaction, p27Kip1 might modulate stathmin activity indirectly through its inhibitory effects on cyclin–CDK complexes. As stathmin is a substrate for CDK1, inhibition of CDK1 by p27Kip1 might prevent the inactivation of stathmin and lead to destabilization of microtubules. Alternatively, the inhibition of cyclin–CDK complexes by p27Kip1 might regulate stathmin function by a different mechanism. Because E2F transcription factors
p27 (ii)
Rac
(iii)
(iv)
(i)
CDKs
hKIS
E2F Stathmin
Microtubules
Migration
Proliferation
TRENDS in Cell Biology
Figure 1. Potential interactions between p27Kip1 and stathmin in the regulation of cell motility. Stathmin regulates microtubule dynamics during cell proliferation and cell migration. Changes in the expression and/or phosphorylation of stathmin could result in changes in microtubule stability, which lead to either inhibition or stimulation of cell motility. p27Kip1 has the potential for modulating stathmin expression and/or function through at least four different mechanisms: (i) p27Kip1 might directly interact with stathmin and prevent its microtubule-destabilizing activity [1]; (ii) p27Kip1 activates Rac [3], which can promote the phosphorylation of stathmin and inhibit its microtubule-destabilizing activity [14]; (iii) the inhibitory effect of p27Kip1 on cyclin-dependent kinases (CDKs) might result in either E2Fmediated downregulation of stathmin expression [15] or increased stathmin activity by means of CDK1 inactivation; (iv) p27Kip1 and stathmin might interact through the human kinase interacting stathmin (hKIS) that phosphorylates p27Kip1 and induces its translocation to the cytoplasm where stathmin is localized.
348
Update
TRENDS in Cell Biology
are known to activate the stathmin promoter [15], inhibition of the CDK–Rb–E2F pathway by p27Kip1 might result in decreased stathmin expression and lead to microtubule stabilization. Finally, a fourth way in which p27Kip1 and stathmin might interact is through the human kinase interacting stathmin (hKIS). This kinase was first discovered as a stathmin partner protein and later shown to phosphorylate stathmin. Interestingly, KIS was recently shown to phosphorylate p27Kip1 and promote its translocation from the nucleus to the cytoplasm, where it has to be to regulate the activity of stathmin.
Concluding remarks The description of a role for the physical interaction between p27Kip1 and stathmin in the regulation of cell motility is an important discovery that requires confirmation by other investigators. This discovery should encourage the investigation of other ways in which these two molecules might interact to regulate cell motility and possibly the cell cycle. It should be emphasized that all the indirect interactions that we described above are purely speculative and none has been verified experimentally. Nonetheless, the studies of Baldassarre and colleagues have already introduced a provocative new twist in our understanding of the regulation of cell motility and have brought together two players that had not shared the same stage before.
Vol.15 No.7 July 2005
References 1 Baldassarre, G. et al. (2005) p27Kip1-stathmin interaction influences sarcoma cell migration and invasion. Cancer Cell 7, 51–63 2 Denicourt, C. and Dowdy, S.F. (2004) Cip/Kip proteins: more than just CDKs inhibitors. Genes Dev. 18, 851–855 3 McAllister, S.S. et al. (2003) Novel p27Kip1 C-terminal scatter domain mediates Rac-dependent cell migration independent of cell cycle arrest functions. Mol. Cell. Biol. 23, 216–228 4 Besson, A. et al. (2004) p27Kip1 modulates cell migration through the regulation of RhoA activation. Genes Dev. 18, 862–876 5 Goukassian, D. et al. (2001) Overexpression of p27Kip1 by doxycyclineregulated adenoviral vectors inhibits endothelial cell proliferation and migration and impairs angiogenesis. FASEB J. 15, 1877–1885 6 Sun, J. et al. (2001) Role for p27Kip1 in vascular smooth muscle cell migration. Circulation 103, 2967–2972 7 Rubin, C.I. and Atweh, G.F. (2004) The role of stathmin in the regulation of the cell cycle. J. Cell. Biochem. 93, 242–250 8 Desai, A. and Mitchison, T.J. (1997) Microtubule polymerization dynamics. Annu. Rev. Cell Dev. Biol. 13, 83–117 9 Howell, B. et al. (1999) Dissociation of the tubulin-sequestering and microtubule catastrophe-promoting activities of oncoprotein 18/stathmin. Mol. Biol. Cell 10, 105–118 10 Ozon, S. et al. (2002) Drosophila stathmin: a microtubule-destabilizing factor involved in nervous system formation. Mol. Biol. Cell 13, 698–710 11 Jin, K. et al. (2004) Proteomic and immunochemical characterization of a role for stathmin in adult neurogenesis. FASEB J. 18, 287–299 12 Giampietro, C. et al. (2005) Stathmin expression modulates migratory properties of GN-11 neurons in vitro. Endocrinology 146, 1825–1834 13 Wittmann, T. et al. (2004) Regulation of microtubule destabilizing activity of Op18/stathmin downstream of Rac1. J. Biol. Chem. 279, 6196–6203 14 Niethammer, P. et al. (2004) Stathmin-tubulin interaction gradients in motile and mitotic cells. Science 303, 1862–1866 15 Polzin, R.G. et al. (2004) E2F sites in the Op18 promoter are required for high level of expression in the human prostate carcinoma cell line PC-3-M. Gene 341, 209–218
Acknowledgements We apologize to the authors whose studies were not cited because of space limitation.
0962-8924/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tcb.2005.05.008
Elsevier celebrates two anniversaries with gift to university libraries in the developing world In 1580, the Elzevir family began their printing and bookselling business in the Netherlands, publishing works by scholars such as John Locke, Galileo Galilei and Hugo Grotius. On 4 March 1880, Jacobus George Robbers founded the modern Elsevier company intending, just like the original Elzevir family, to reproduce fine editions of literary classics for the edification of others who shared his passion, other ’Elzevirians’. Robbers co-opted the Elzevir family’s old printer’s mark, visually stamping the new Elsevier products with a classic old symbol of the symbiotic relationship between publisher and scholar. Elsevier has since become a leader in the dissemination of scientific, technical and medical (STM) information, building a reputation for excellence in publishing, new product innovation and commitment to its STM communities. In celebration of the House of Elzevir’s 425th anniversary and the 125th anniversary of the modern Elsevier company, Elsevier will donate books to 10 university libraries in the developing world. Entitled ‘A Book in Your Name’, each of the 6 700 Elsevier employees worldwide has been invited to select one of the chosen libraries to receive a book donated by Elsevier. The core gift collection contains the company’s most important and widely used STM publications including Gray’s Anatomy, Dorland’s Illustrated Medical Dictionary, Essential Medical Physiology, Cecil Essentials of Medicine, Mosby’s Medical, Nursing and Allied Health Dictionary, The Vaccine Book, Fundamentals of Neuroscience, and Myles Textbook for Midwives. The 10 beneficiary libraries are located in Africa, South America and Asia. They include the Library of the Sciences of the University of Sierra Leone; the library of the Muhimbili University College of Health Sciences of the University of Dar es Salaam, Tanzania; the library of the College of Medicine of the University of Malawi; and the libraries of the University of Zambia, Universite du Mali, Universidade Eduardo Mondlane, Mozambique; Makerere University, Uganda; Universidad San Francisco de Quito, Ecuador; Universidad Francisco Marroquin, Guatemala; and the National Centre for Scientific and Technological Information (NACESTI), Vietnam. Through ‘A Book in Your Name’, the 10 libraries will receive approximately 700 books at a retail value of approximately 1 million US dollars.
For more information, visit www.elsevier.com www.sciencedirect.com