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Piotr Sicinski - One of the best experts on this subject based on the ideXlab platform.
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E-type cyclins modulate telomere integrity in mammalian male meiosis
Chromosoma, 2016Co-Authors: Marcia Manterola, Piotr Sicinski, Debra J. WolgemuthAbstract:We have shown that E-type cyclins are key regulators of mammalian male meiosis. Depletion of cyclin E2 reduced fertility in male mice due to meiotic defects, involving abnormal pairing and synapsis, unrepaired DNA, and loss of telomere structure. These defects were exacerbated by additional loss of cyclin E1, and complete absence of both E-type cyclins produces a meiotic catastrophe. Here, we investigated the involvement of E-type cyclins in maintaining telomere integrity in male meiosis. Spermatocytes lacking cyclin E2 and one E1 allele ( E1+/-E2-/- ) displayed a high rate of telomere abnormalities but can progress to pachytene and diplotene stages. We show that their telomeres exhibited an aberrant DNA damage repair response during pachynema and that the shelterin complex proteins TRF2 and RAP2 were significantly decreased in the proximal telomeres. Moreover, the insufficient level of these proteins correlated with an increase of γ-H2AX foci in the affected telomeres and resulted in telomere associations involving TRF1 and telomere detachment in later prophase-I stages. These results suggest that E-type cyclins are key modulators of telomere integrity during meiosis by, at least in part, maintaining the balance of shelterin complex proteins, and uncover a novel role of E-type cyclins in regulating chromosome structure during male meiosis.
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non canonical functions of cell cycle cyclins and cyclin dependent kinases
Nature Reviews Molecular Cell Biology, 2016Co-Authors: Per Hydbring, Marcos Malumbres, Piotr SicinskiAbstract:Mammalian cyclins and cyclin-dependent kinases (CDKs) have non-canonical, cell cycle-independent functions in processes such as transcription and DNA damage repair. Through these and other activities, they regulate cell death, differentiation, the immune response and metabolism. The roles of cyclins and their catalytic partners, the cyclin-dependent kinases (CDKs), as core components of the machinery that drives cell cycle progression are well established. Increasing evidence indicates that mammalian cyclins and CDKs also carry out important functions in other cellular processes, such as transcription, DNA damage repair, control of cell death, differentiation, the immune response and metabolism. Some of these non-canonical functions are performed by cyclins or CDKs, independently of their respective cell cycle partners, suggesting that there was a substantial divergence in the functions of these proteins during evolution.
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mammalian e type cyclins control chromosome pairing telomere stability and cdk2 localization in male meiosis
PLOS Genetics, 2014Co-Authors: Laetitia Martinerie, Piotr Sicinski, Yan Geng, Marcia Manterola, Sanny S W Chung, Sunil K Panigrahi, Melissa M Weisbach, Ana Vasileva, Debra J. WolgemuthAbstract:Loss of function of cyclin E1 or E2, important regulators of the mitotic cell cycle, yields viable mice, but E2-deficient males display reduced fertility. To elucidate the role of E-type cyclins during spermatogenesis, we characterized their expression patterns and produced additional deletions of Ccne1 and Ccne2 alleles in the germline, revealing unexpected meiotic functions. While Ccne2 mRNA and protein are abundantly expressed in spermatocytes, Ccne1 mRNA is present but its protein is detected only at low levels. However, abundant levels of cyclin E1 protein are detected in spermatocytes deficient in cyclin E2 protein. Additional depletion of E-type cyclins in the germline resulted in increasingly enhanced spermatogenic abnormalities and corresponding decreased fertility and loss of germ cells by apoptosis. Profound meiotic defects were observed in spermatocytes, including abnormal pairing and synapsis of homologous chromosomes, heterologous chromosome associations, unrepaired double-strand DNA breaks, disruptions in telomeric structure and defects in cyclin-dependent-kinase 2 localization. These results highlight a new role for E-type cyclins as important regulators of male meiosis.
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Genetic replacement of cyclin D1 function in mouse development by cyclin D2.
Molecular and Cellular Biology, 2005Co-Authors: Bradley C. Carthon, Carola A. Neumann, Tiansen Li, Basil S Pawlyk, Yan Geng, Piotr SicinskiAbstract:The progression of mammalian cells through the G1 phase of the cell cycle is driven by the D-type and E-type cyclins (43). These cyclins bind, activate, and provide substrate specificity for their associated cyclin-dependent kinases (CDKs). In contrast to other cyclins, which are induced periodically during cell cycle progression, the expression of D cyclins is controlled largely by the extracellular environment. For this reason, D cyclins are regarded as links between the external mitogenic milieu and the core cell cycle machinery (39, 45). Three D-type cyclins, D1, D2 and D3, have been enumerated in mammalian cells (21, 33, 34, 37, 38, 57). These three proteins are encoded by separate genes located on different chromosomes, but they show significant amino acid similarity, suggesting that they arose from a common primordial ancestor gene (19, 58). On average, D cyclins show 50 to 60% identity throughout the entire coding sequence and 75 to 78% identity within the most conserved cyclin box domain (19, 58). All three D cyclins associate with CDK4 or CDK6, yielding six different combinations of cyclin D-CDK holoenzymes (2, 10, 20, 31, 32, 36). An important issue is whether each of the D cyclins performs unique, possibly cell type-specific functions or the three proteins represent tissue-specific isoforms with virtually identical functions. At a biochemical level, all three D cyclins were shown to physically associate with CDK4 and CDK6 and to drive phosphorylation of the retinoblastoma protein, pRB, and pRB-related “pocket” proteins p107 and p130 (3, 28, 32, 36, 54, 56). The phosphorylation of these pocket proteins may represent the major function for cyclin D-CDK complexes in cell cycle progression, as shown by the observations that cells lacking pRB or p107 and p130 no longer require D cyclins for proliferation (1, 4, 16, 23, 29, 35, 40, 53). However, biochemical differences between the three D cyclins were noted. Thus, cyclins D2 and D3 can form active complexes with CDK2, while cyclin D1 was reported to lack this ability (10, 17). Moreover, in addition to their well-established CDK-dependent functions, D cyclins were shown to interact with tissue-specific transcription factors, such as estrogen receptor, androgen receptor, thyroid receptor, and retinoic acid receptor alpha, C/EBP binding protein β, DMP1, and others (8, 27). In some cases, this interaction was uniquely ascribed to a particular D-type cyclin (9, 60). To address the functions of the D-type cyclins in development, we and others generated mice lacking cyclin D1, D2, or D3 and characterized their phenotypes (12, 46-48). We found that mice lacking individual D cyclins were viable and displayed narrow, tissue-specific abnormalities. For instance, cyclin D1-deficient mice showed underdeveloped, hypoplastic retinas and presented a developmental neurological abnormality. Moreover, cyclin D1-deficient females displayed a normal mammary epithelial tree at the end of sexual maturation, but they failed to undergo full lobuloalveolar development during pregnancy (12, 48). Importantly, all these compartments developed normally in cyclin D2- or D3-deficient animals (46, 47), revealing a unique requirement for cyclin D1 in vivo in selected tissues. In the present study, we asked whether the requirement for cyclin D1 function in these compartments was caused by tissue-specific pattern of D cyclin expression or alternatively reflected the presence of specialized tissue-specific functions for cyclin D1. To address this question by genetic means, we generated a knock-in strain of mice expressing cyclin D2 in place of cyclin D1. We next asked whether cyclin D2 could drive the normal development of cyclin D1-dependent tissues.
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cyclin e ablation in the mouse
Cell, 2003Co-Authors: Yan Geng, Qunyan Yu, Jurgen E Schneider, William M Rideout, Humphrey Gardner, Shoumo Bhattacharya, Ewa Sicinska, Roderick T Bronson, Piotr SicinskiAbstract:Abstract E type cyclins (E1 and E2) are believed to drive cell entry into the S phase. It is widely assumed that the two E type cyclins are critically required for proliferation of all cell types. Here, we demonstrate that E type cyclins are largely dispensable for mouse development. However, endoreplication of trophoblast giant cells and megakaryocytes is severely impaired in the absence of cyclin E. Cyclin E-deficient cells proliferate actively under conditions of continuous cell cycling but are unable to reenter the cell cycle from the quiescent G 0 state. Molecular analyses revealed that cells lacking cyclin E fail to normally incorporate MCM proteins into DNA replication origins during G 0 →S progression. We also found that cyclin E-deficient cells are relatively resistant to oncogenic transformation. These findings define a molecular function for E type cyclins in cell cycle reentry and reveal a differential requirement for cyclin E in normal versus oncogenic proliferation.
Debra J. Wolgemuth - One of the best experts on this subject based on the ideXlab platform.
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E-type cyclins modulate telomere integrity in mammalian male meiosis
Chromosoma, 2016Co-Authors: Marcia Manterola, Piotr Sicinski, Debra J. WolgemuthAbstract:We have shown that E-type cyclins are key regulators of mammalian male meiosis. Depletion of cyclin E2 reduced fertility in male mice due to meiotic defects, involving abnormal pairing and synapsis, unrepaired DNA, and loss of telomere structure. These defects were exacerbated by additional loss of cyclin E1, and complete absence of both E-type cyclins produces a meiotic catastrophe. Here, we investigated the involvement of E-type cyclins in maintaining telomere integrity in male meiosis. Spermatocytes lacking cyclin E2 and one E1 allele ( E1+/-E2-/- ) displayed a high rate of telomere abnormalities but can progress to pachytene and diplotene stages. We show that their telomeres exhibited an aberrant DNA damage repair response during pachynema and that the shelterin complex proteins TRF2 and RAP2 were significantly decreased in the proximal telomeres. Moreover, the insufficient level of these proteins correlated with an increase of γ-H2AX foci in the affected telomeres and resulted in telomere associations involving TRF1 and telomere detachment in later prophase-I stages. These results suggest that E-type cyclins are key modulators of telomere integrity during meiosis by, at least in part, maintaining the balance of shelterin complex proteins, and uncover a novel role of E-type cyclins in regulating chromosome structure during male meiosis.
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mammalian e type cyclins control chromosome pairing telomere stability and cdk2 localization in male meiosis
PLOS Genetics, 2014Co-Authors: Laetitia Martinerie, Piotr Sicinski, Yan Geng, Marcia Manterola, Sanny S W Chung, Sunil K Panigrahi, Melissa M Weisbach, Ana Vasileva, Debra J. WolgemuthAbstract:Loss of function of cyclin E1 or E2, important regulators of the mitotic cell cycle, yields viable mice, but E2-deficient males display reduced fertility. To elucidate the role of E-type cyclins during spermatogenesis, we characterized their expression patterns and produced additional deletions of Ccne1 and Ccne2 alleles in the germline, revealing unexpected meiotic functions. While Ccne2 mRNA and protein are abundantly expressed in spermatocytes, Ccne1 mRNA is present but its protein is detected only at low levels. However, abundant levels of cyclin E1 protein are detected in spermatocytes deficient in cyclin E2 protein. Additional depletion of E-type cyclins in the germline resulted in increasingly enhanced spermatogenic abnormalities and corresponding decreased fertility and loss of germ cells by apoptosis. Profound meiotic defects were observed in spermatocytes, including abnormal pairing and synapsis of homologous chromosomes, heterologous chromosome associations, unrepaired double-strand DNA breaks, disruptions in telomeric structure and defects in cyclin-dependent-kinase 2 localization. These results highlight a new role for E-type cyclins as important regulators of male meiosis.
Nikola P. Pavletich - One of the best experts on this subject based on the ideXlab platform.
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Structural basis of inhibition of CDK–cyclin complexes by INK4 inhibitors
Genes & Development, 2000Co-Authors: Philip D. Jeffrey, Lily Tong, Nikola P. PavletichAbstract:Cyclin-dependent kinases (CDKs) are a family of closely related Ser/Thr protein kinases that coordinate the cell's progression through the cell cycle by switching between active and inactive states. CDKs, inactive in the monomeric state, are activated by the binding of cyclins, which impart basal activity to the kinase, and by phosphorylation, which fully activates the kinase. CDKs are inactivated by the binding of CDK inhibitors (CKIs) or by additional phosphorylation (for review, see Morgan 1995; Pavletich 1999). The closely related cyclinD-dependent kinases Cdk4 and Cdk6 drive the cell's progression through the G1 phase of the cell cycle. G1 progression is dependent on extracellular mitogenic signals that activate Cdk4/6 by up-regulating levels of their cyclinD activators (Sherr 1994). Cdk4/6 in turn can be inactivated by the INK4 family of CKIs, which are induced by a variety of antiproliferative signals such as TGF-β (p15INK4b), senescence (p16INK4a), and terminal differentiation (p18INK4c and p19INK4d) (for review, see Sherr and Roberts 1999). Cdk4/6 and their regulators have a central role in the control of cell proliferation (Sherr 1996), as underscored by their frequent alteration in cancer (for review, see Hall and Peters 1996): An INK4 inhibitor, p16INK4a (p16), is a tumor suppressor that is altered in >50% of certain tumor types (Kamb et al. 1994; Nobori et al. 1994; Hall and Peters 1996); cyclinD is often amplified in breast and prostate cancer (Hall and Peters 1996); mutations in Cdk4 that render it refractory to inhibition by INK4 have been identified in several cancer cases (Wolfel et al. 1995; Zuo et al. 1996). In addition, certain γ herpes viruses including Kaposi's sarcoma-associated herpes virus (KSHV/HHV8; Chang et al. 1994) express an oncogenic D-type cyclin that can bind to and activate Cdk4/6 and contribute to the deregulation of the cell cycle (Godden-Kent et al. 1997; Li et al. 1997). INK4 inhibitors can bind both monomeric Cdk4/6 (Serrano et al. 1993; Hall et al. 1995; Parry et al. 1995) and cyclinD-bound Cdk4/6 (Hirai et al. 1995; Adachi et al. 1997; Reynisdottir and Massague 1997) and appear to use multiple mechanisms to inhibit the CDK and halt the progression of the cell cycle. INK4 binding to the monomeric Cdk4/6 subunit interferes with the subsequent binding of cyclinD and renders the CDK nonactivatable (Parry et al. 1995; Guan et al. 1996; McConnell et al. 1999). This is, at least in part, because of the requirement of an Hsp90–Cdc37 heat shock protein complex for the assembly of the Cdk4/6–cyclinD complex (Stepanova et al. 1996) and the ability of INK4s to compete with Cdc37 binding to Cdk4/6 (Lamphere et al. 1997; Russo et al. 1998). However, if the Cdk4/6–cyclinD complex is assembled first, INK4s can bind the Cdk4/6–cyclin complex and inhibit it without dissociating the cyclin (Hirai et al. 1995; Adachi et al. 1997). The relative contribution of these two INK4 activities to cell cycle arrest has been a point of debate, as several studies have shown that the majority of p16 is found in binary complexes with Cdk4/6 in vivo (Parry et al. 1995; McConnell et al. 1999). However, it has also been shown that induction of p15INK4b or p19INK4d (p19) to levels that arrest cell growth results in the formation of INK4–cyclinD–Cdk4/6 complexes without causing immediate dissociation of cyclinD from Cdk4/6 (Adachi et al. 1997; Reynisdottir and Massague 1997). Previous crystallographic studies of the p16–Cdk6 (Russo et al. 1998) and p19–Cdk6 (Brotherton et al. 1998; Russo et al. 1998) binary complexes showed how these inhibitors bind the monomeric CDK and, in comparison with structures of monomeric Cdk2 (De Bondt et al. 1993) and Cdk2–cyclinA complexes (Jeffrey et al. 1995; Russo et al. 1996), showed that INK4 binding to Cdk6 caused conformational changes that distorted the catalytic cleft and allosterically altered the cyclin binding site. However, the way in which INK4s bind the preformed CDK–cyclin complex, how they inhibit its activity, and how the cyclin remains bound to the CDK has not been clear. To address these questions, we have determined the structure of a p18INK4c–Cdk6–D-type cyclin ternary complex. We used the D-type cyclin encoded by the Kaposi's sarcoma–associated herpesvirus (K-cyclin; Godden-Kent et al. 1997; Li et al. 1997), as we were not able to produce a cellular D-type cyclin in a form suitable for crystallization. The Cdk6–K-cyclin complex has been shown to be resistant to inhibition by INK4s (Swanton et al. 1997), but in this study, we show that when Cdk6 is unphosphorylated, the Cdk6–K-cyclin complex is susceptible to inhibition by INK4s. The structure of the ternary p18–Cdk6–K-cyclin complex shows that Cdk6 adopts a conformation where residues involved in ATP binding and catalysis are misaligned. This active site distortion is similar to that seen in the binary INK4–Cdk6 complexes. The cyclin-binding site is also distorted, with the cyclin remaining bound in a nonfunctional way, via an interface that is 30% smaller in size. This suggests that INK4 binding reduces the stability of the CDK–cyclin interface. The structure also provides insights into how phosphorylated Cdk6 bound to the viral cyclin may evade inhibition by INK4s.
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structural basis of inhibition of cdk cyclin complexes by ink4 inhibitors
Genes & Development, 2000Co-Authors: Philip D. Jeffrey, Lily Tong, Nikola P. PavletichAbstract:Cyclin-dependent kinases (CDKs) are a family of closely related Ser/Thr protein kinases that coordinate the cell's progression through the cell cycle by switching between active and inactive states. CDKs, inactive in the monomeric state, are activated by the binding of cyclins, which impart basal activity to the kinase, and by phosphorylation, which fully activates the kinase. CDKs are inactivated by the binding of CDK inhibitors (CKIs) or by additional phosphorylation (for review, see Morgan 1995; Pavletich 1999). The closely related cyclinD-dependent kinases Cdk4 and Cdk6 drive the cell's progression through the G1 phase of the cell cycle. G1 progression is dependent on extracellular mitogenic signals that activate Cdk4/6 by up-regulating levels of their cyclinD activators (Sherr 1994). Cdk4/6 in turn can be inactivated by the INK4 family of CKIs, which are induced by a variety of antiproliferative signals such as TGF-β (p15INK4b), senescence (p16INK4a), and terminal differentiation (p18INK4c and p19INK4d) (for review, see Sherr and Roberts 1999). Cdk4/6 and their regulators have a central role in the control of cell proliferation (Sherr 1996), as underscored by their frequent alteration in cancer (for review, see Hall and Peters 1996): An INK4 inhibitor, p16INK4a (p16), is a tumor suppressor that is altered in >50% of certain tumor types (Kamb et al. 1994; Nobori et al. 1994; Hall and Peters 1996); cyclinD is often amplified in breast and prostate cancer (Hall and Peters 1996); mutations in Cdk4 that render it refractory to inhibition by INK4 have been identified in several cancer cases (Wolfel et al. 1995; Zuo et al. 1996). In addition, certain γ herpes viruses including Kaposi's sarcoma-associated herpes virus (KSHV/HHV8; Chang et al. 1994) express an oncogenic D-type cyclin that can bind to and activate Cdk4/6 and contribute to the deregulation of the cell cycle (Godden-Kent et al. 1997; Li et al. 1997). INK4 inhibitors can bind both monomeric Cdk4/6 (Serrano et al. 1993; Hall et al. 1995; Parry et al. 1995) and cyclinD-bound Cdk4/6 (Hirai et al. 1995; Adachi et al. 1997; Reynisdottir and Massague 1997) and appear to use multiple mechanisms to inhibit the CDK and halt the progression of the cell cycle. INK4 binding to the monomeric Cdk4/6 subunit interferes with the subsequent binding of cyclinD and renders the CDK nonactivatable (Parry et al. 1995; Guan et al. 1996; McConnell et al. 1999). This is, at least in part, because of the requirement of an Hsp90–Cdc37 heat shock protein complex for the assembly of the Cdk4/6–cyclinD complex (Stepanova et al. 1996) and the ability of INK4s to compete with Cdc37 binding to Cdk4/6 (Lamphere et al. 1997; Russo et al. 1998). However, if the Cdk4/6–cyclinD complex is assembled first, INK4s can bind the Cdk4/6–cyclin complex and inhibit it without dissociating the cyclin (Hirai et al. 1995; Adachi et al. 1997). The relative contribution of these two INK4 activities to cell cycle arrest has been a point of debate, as several studies have shown that the majority of p16 is found in binary complexes with Cdk4/6 in vivo (Parry et al. 1995; McConnell et al. 1999). However, it has also been shown that induction of p15INK4b or p19INK4d (p19) to levels that arrest cell growth results in the formation of INK4–cyclinD–Cdk4/6 complexes without causing immediate dissociation of cyclinD from Cdk4/6 (Adachi et al. 1997; Reynisdottir and Massague 1997). Previous crystallographic studies of the p16–Cdk6 (Russo et al. 1998) and p19–Cdk6 (Brotherton et al. 1998; Russo et al. 1998) binary complexes showed how these inhibitors bind the monomeric CDK and, in comparison with structures of monomeric Cdk2 (De Bondt et al. 1993) and Cdk2–cyclinA complexes (Jeffrey et al. 1995; Russo et al. 1996), showed that INK4 binding to Cdk6 caused conformational changes that distorted the catalytic cleft and allosterically altered the cyclin binding site. However, the way in which INK4s bind the preformed CDK–cyclin complex, how they inhibit its activity, and how the cyclin remains bound to the CDK has not been clear. To address these questions, we have determined the structure of a p18INK4c–Cdk6–D-type cyclin ternary complex. We used the D-type cyclin encoded by the Kaposi's sarcoma–associated herpesvirus (K-cyclin; Godden-Kent et al. 1997; Li et al. 1997), as we were not able to produce a cellular D-type cyclin in a form suitable for crystallization. The Cdk6–K-cyclin complex has been shown to be resistant to inhibition by INK4s (Swanton et al. 1997), but in this study, we show that when Cdk6 is unphosphorylated, the Cdk6–K-cyclin complex is susceptible to inhibition by INK4s. The structure of the ternary p18–Cdk6–K-cyclin complex shows that Cdk6 adopts a conformation where residues involved in ATP binding and catalysis are misaligned. This active site distortion is similar to that seen in the binary INK4–Cdk6 complexes. The cyclin-binding site is also distorted, with the cyclin remaining bound in a nonfunctional way, via an interface that is 30% smaller in size. This suggests that INK4 binding reduces the stability of the CDK–cyclin interface. The structure also provides insights into how phosphorylated Cdk6 bound to the viral cyclin may evade inhibition by INK4s.
C. Elizabeth Caldon - One of the best experts on this subject based on the ideXlab platform.
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Cyclin E2 is the predominant E-cyclin associated with NPAT in breast cancer cells
Cell Division, 2015Co-Authors: Samuel Rogers, Claudio Marcelo Sergio, Andrew Burgess, E A Musgrove, Marcel E. Dinger, Brian S. Gloss, C. Elizabeth CaldonAbstract:Background The cyclin E oncogene activates CDK2 to drive cells from G_1 to S phase of the cell cycle to commence DNA replication. It coordinates essential cellular functions with the cell cycle including histone biogenesis, splicing, centrosome duplication and origin firing for DNA replication. The two E-cyclins, E1 and E2, are assumed to act interchangeably in these functions. However recent reports have identified unique functions for cyclins E1 and E2 in different tissues, and particularly in breast cancer. Findings Cyclins E1 and E2 localise to distinct foci in breast cancer cells as well as co-localising within the cell. Both E-cyclins are found in complex with CDK2, at centrosomes and with the splicing machinery in nuclear speckles. However cyclin E2 uniquely co-localises with NPAT, the main activator of cell-cycle regulated histone transcription. Increased cyclin E2, but not cyclin E1, expression is associated with high expression of replication-dependent histones in breast cancers. Conclusions The preferential localisation of cyclin E1 or cyclin E2 to distinct foci indicates that each E-cyclin has unique roles. Cyclin E2 uniquely interacts with NPAT in breast cancer cells, and is associated with higher levels of histones in breast cancer. This could explain the unique correlations of high cyclin E2 expression with poor outcome and genomic instability in breast cancer.
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Distinct and redundant functions of cyclin E1 and cyclin E2 in development and cancer
Cell Division, 2010Co-Authors: C. Elizabeth Caldon, E A MusgroveAbstract:The highly conserved E-type cyclins are core components of the cell cycle machinery, facilitating the transition into S phase through activation of the cyclin dependent kinases, and assembly of pre-replication complexes on DNA. Cyclin E1 and cyclin E2 are assumed to be functionally redundant, as cyclin E1^-/- E2^-/- mice are embryonic lethal while cyclin E1^-/- and E2^-/- single knockout mice have primarily normal phenotypes. However more detailed studies of the functions and regulation of the E-cyclins have unveiled potential additional roles for these proteins, such as in endoreplication and meiosis, which are more closely associated with either cyclin E1 or cyclin E2. Moreover, expression of each E-cyclin can be independently regulated by distinct transcription factors and microRNAs, allowing for context-specific expression. Furthermore, cyclins E1 and E2 are frequently expressed independently of one another in human cancer, with unique associations to signatures of poor prognosis. These data imply an absence of co-regulation of cyclins E1 and E2 during tumorigenesis and possibly different contributions to cancer progression. This is supported by in vitro data identifying divergent regulation of the two genes, as well as potentially different roles in vivo .
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Estrogen Regulation of Cyclin E2 Requires Cyclin D1 but Not c-Myc
Molecular and Cellular Biology, 2009Co-Authors: C. Elizabeth Caldon, C. Marcelo Sergio, Judith Schütte, Marijke N. Boersma, Jason S. Carroll, Robert L. Sutherland, E A MusgroveAbstract:During estrogen-induced proliferation, c-Myc and cyclin D1 initiate independent pathways that activate cyclin E1-Cdk2 by sequestration and/or downregulation of the CDK inhibitor p21Waf1/Cip1, without significant increases in cyclin E1 protein levels. In contrast, cyclin E2 undergoes a marked increase in expression, which occurs within 9 to 12 h of estrogen treatment of antiestrogen-pretreated MCF-7 breast cancer cells. Both E cyclins are important to estrogen action, as small interfering RNA (siRNA)-mediated knockdown of either cyclin E1 or cyclin E2 attenuated estrogen-mediated proliferation. Inducible expression of cyclin D1 upregulated cyclin E2, while siRNA-mediated knockdown of cyclin D1 attenuated estrogen effects on cyclin E2. However, manipulation of c-Myc levels did not profoundly affect cyclin E2. Cyclin E2 induction by estrogen was accompanied by recruitment of E2F1 to the cyclin E1 and E2 promoters, and cyclin D1 induction was sufficient for E2F1 recruitment. siRNA-mediated knockdown of the chromatin remodelling factor CHD8 prevented cyclin E2 upregulation. Together, these data indicate that cyclin E2-Cdk2 activation by estrogen occurs via E2F- and CHD8-mediated transcription of cyclin E2 downstream of cyclin D1. This contrasts with the predominant regulation of cyclin E1-Cdk2 activity via CDK inhibitor association downstream of both c-Myc and cyclin D1 and indicates that cyclins E1 and E2 are not always coordinately regulated.
Jae U. Jung - One of the best experts on this subject based on the ideXlab platform.
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Crystal structure of a viral cyclin, a positive regulator of cyclin-dependent kinase 6.
Structure, 1999Co-Authors: Ursula Schulze-gahmen, Jae U. JungAbstract:BACKGROUND: Cyclin-dependent kinases (CDKs) have a central role in cell-cycle control and are activated by complex formation with positive regulatory proteins called cyclins and by phosphorylation. The overexpression and mutation of cyclins and CDKs has been associated with tumorigenesis and oncogenesis. A virus-encoded cyclin (v-cyclin) from herpesvirus saimiri has been shown to exhibit highest sequence homology to type D cyclins and specifically activates CDK6 of host cells to a very high degree. RESULTS: We have determined the first X-ray structure of a v-cyclin to 3.0 A resolution. The structure of the core domains is very similar to those of cyclin A and cyclin H from human cells. To understand the structural basis for the v-cyclin specificity for CDK6 and the insensitivity of the complex to inhibitors of the p21 and INK4 families, a v-cyclin-CDK2 model was built on the basis of the known structures of human cyclin A in complex with CDK2 and the CDK inhibitor p27(Kip1). CONCLUSIONS: Although many critical interactions between cyclin A and CDK2 would be conserved in a v-cyclin-CDK2 complex, some appear sterically or electrostatically unfavorable due to shifts in the backbone conformation or sidechain differences and may contribute to v-cyclin selectivity for CDK6. The insensitivity of v-cyclin-CDK6 complexes to inhibitors of the p21 family is probably due to structural changes in v-cyclin that lead to a flatter surface area offering fewer potential contacts with the protein inhibitor. In addition, sequence changes in v-cyclin eliminate hydrogen-bonding partners for atoms of the p27(Kip1) inhibitor. This structure provides the first model for interactions between v-cyclins and host cell-cycle proteins; these interactions may be important for virus survival as well as oncogenic transformation of host cells.
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Virus-encoded cyclin.
Molecular and Cellular Biology, 1994Co-Authors: Jae U. Jung, Maria Stager, Ronald C. DesrosiersAbstract:: Herpesvirus saimiri contains an open reading frame called eclf2 with homology to the cellular type D cyclins. We now show that the eclf2 gene product is a novel virus-encoded cyclin (v-cyclin). The protein encoded by the v-cyclin gene of this oncogenic herpesvirus was found to have an apparent molecular size of 29 kDa in transformed cells. v-Cyclin protein was found to be associated with cdk6, a cellular cyclin-dependent kinase known to interact with cellular type D cyclins. cdk6/v-cyclin complexes strongly phosphorylated Rb fusion protein and histone H1 as substrates in vitro. Mutational analyses showed that highly conserved amino acids in the cyclin box of v-cyclin were important for association with cdk6 and for activation of cdk6 kinase activity. Thus, v-cyclin resembles cellular type D cyclins in primary sequence, in its association with cdk6, by its ability to activate protein kinase activity, and by the presence of functional cyclin box sequences. v-Cyclin exhibited a selective preference for association with cdk6 over other cyclin-dependent kinases and a high level of kinase activation. The properties of v-cyclin suggest a likely role in oncogenic transformation by this T-lymphotropic herpesvirus.
