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Piotr Sicinski - One of the best experts on this subject based on the ideXlab platform.
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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: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. In addition to their well-established functions in driving cell proliferation, cell cycle proteins have several non-canonical roles. D-type Cyclins and their partner cyclin-dependent kinase 6 (CDK6) have direct, kinase-independent roles in augmenting or repressing gene expression. In mammalian cells, cyclin D1 promotes, whereas cyclin A–CDK2 inhibits, DNA double-strand break (DSB) repair through homologous recombination. In yeast, CDK activity seems to dictate the choice of DSB repair between non-homologous end-joining and homologous recombination. Cyclins are postulated to regulate apoptosis, autophagy and anoikis. Analyses of mice lacking D-type Cyclins support pro-survival roles for these proteins in specific tissues. Cyclin D1, CDK6 and the CDK inhibitor p27 (KIP1) can affect the actin cytoskeleton and cell migration through several mechanisms. Cell cycle proteins have important roles in development and have important functions in the nervous system and in regulating the immune response. Cyclins and CDKs are shown or postulated to regulate metabolism through different routes, including a direct role in controlling mitochondrial function. 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.
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differences in regulation and function of e Cyclins in human cancer cells
Cell Cycle, 2013Co-Authors: Yan Geng, Piotr SicinskiAbstract:Mammalian cyclin E was cloned by groups of James Roberts and Steven Reed in a screen for human cDNAs which can complement mutant G1 cyclin genes CLN1, CLN2 and CLN3 in yeast Sacaromyces cerevisiae.1 The flurry of studies which followed this discovery demonstrated that in mammalian cells cyclin E is induced in late G1 phase when it activates cyclin-dependent kinase CDK2, and also CDK1 and CDK3. During G1 phase progression cyclin E-CDK2 kinase phosphorylates and inactivates the retinoblastoma protein, pRB, leading to activation of E2F transcription factors. Since the cyclin E gene represents one of E2F transcriptional targets, this mechanism creates a positive feedback loop which leads to full activation of cyclin E-CDK2 kinase. Once induced, cyclin E-CDK2 phosphorylates proteins governing cell cycle progression (pRB, p27Kip1, E2F5), centrosome duplication (NPM, CP110), histone gene transcription (NPAT) and others. Cyclin E and cyclin E-CDK2 kinase activity is essential for assembly of DNA pre-replication complexes and for firing of DNA replication origins. As the S phase progresses, cyclin E becomes phosphorylated by cyclin E-CDK2 and by GSK3, and is then targeted for proteosomal degradation by the SCFFbw7 ubiquitin ligase.1 Subsequently, groups of Bruno Amati, Yue Xiong and Steve Coats isolated the second mammalian E-type cyclin, which was termed cyclin E2, while the protein known as “cyclin E” was renamed as cyclin E1. The two E-Cyclins show substantial aminoacid similarity, associate with the same CDK partners, and appear to perform similar biological functions.1 Their regulation seems to be similar, including transcriptional activation by E2F and protein degradation through SCFFbw7 ubiquitin ligase. Also in vivo, the two E-type Cyclins seem to perform highly overlapping set of functions. Thus, genetic ablation of Cyclins E1 or E2 resulted in no major phenotypes, whereas combined loss of both E-Cyclins led to an early embryonic lethality due to placental abnormalities.2 In adult mice, combined ablation of Cyclins E1 and E2 impairs neuronal synaptic function and leads to memory deficits, due to a function of cyclin E in regulating synaptic plasticity.3 Collectively, all these observations suggested that Cyclins E1 and E2 are functionally equivalent. A recent study from Elizabeth Musgrove group4 indicates that this prevailing view may need revisions. The authors focused on the function of overexpressed cyclin E in breast cancer cells. Cyclins E1 and E2 are overexpressed in a substantial number of human cancers, where they contribute to tumorigenesis likely by driving uncontrolled cell cycle progression.1 Moreover, overexpression of cyclin E1 was shown to result in chromosome instability in in vitro cultured cells, and in vivo, in mouse tumors.5,6 While the exact molecular mechanism remains to be elucidated, this role of cyclin E1 is mediated, at least in part, by binding and phosphorylating the anaphase-promoting complex (APC) regulatory subunit, Cdh1.7 This, in turn inhibits APC activity, and results in impaired mitotic progression of cyclin E1-overexpressing cells.7 Unexpectedly, Caldon et al.4 now demonstrate that cyclin E2, when overexpressed, does not interact with Cdh1, does not inhibit APC and does not impair mitotic progression. Yet, cyclin E2 overexpression still triggers genomic instability, as evidenced by increased fraction of abnormal mitoses, as well as the presence of chromosomal aberrations such as chromosome breaks and end-to-end fusions in cyclin E2-overexpressing cells. While the mechanism through which cyclin E2 causes these abnormalities remains unclear, Caldon et al.4 propose that this effect is mediated through inactivation of pRB and pRB-like p107 and p130 proteins by hyperactive cyclin E2-CDK2. Intriguingly, the same group demonstrated that the levels of cyclin E2 in cancer cells are controlled via a distinct mechanism from that operating in normal cells.8 Specifically, while in non-transformed cells the levels of Cyclins E1 and E2 are regulated by SCFFbw7, in a breast cancer cells depletion of Fbw7 affects the levels of cyclin E1, but not E2.8 These finding lead to several questions. Are results of Caldon et al.4,8 generalizable across different types of human cancers? How is the stability of cyclin E2 controlled in cancer cells, and how mechanistically cyclin E2 expression shifts from Fbw7-dependent to -independent mode? How does cyclin E2 trigger chromosomal instability? Analyses of the endogenous protein complexes associated with Cyclins E1 and E2 in cancer cells may help to unravel molecular differences between these two related, but apparently distinct proteins.
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Cyclins d2 and d1 are essential for postnatal pancreatic β cell growth
Molecular and Cellular Biology, 2005Co-Authors: Piotr Sicinski, Ewa Sicinska, Maria A Ciemerych, Jake A Kushner, Lynn M Wartschow, Monica Teta, Simon Y Long, Morris F WhiteAbstract:Regulation of adult -cell mass in pancreatic islets is essential to preserve sufficient insulin secretion in order to appropriately regulate glucose homeostasis. In many tissues mitogens influence development by stimulating D-type Cyclins (D1, D2, or D3) and activating cyclin-dependent kinases (CDK4 or CDK6), which results in progression through the G1 phase of the cell cycle. Here we show that Cyclins D2 and D1 are essential for normal postnatal islet growth. In adult murine islets basal cyclin D2 mRNA expression was easily detected, while cyclin D1 was expressed at lower levels and cyclin D3 was nearly undetectable. Prenatal islet development occurred normally in cyclin D2 / or cyclin D1 / D2 / mice. However, -cell proliferation, adult mass, and glucose tolerance were decreased in adult cyclin D2 / mice, causing glucose intolerance that progressed to diabetes by 12 months of age. Although cyclin D1 / mice never developed diabetes, life-threatening diabetes developed in 3-month-old cyclin D1 / D2 / mice as -cell mass decreased after birth. Thus, Cyclins D2 and D1 were essential for -cell expansion in adult mice. Strategies to tightly regulate D-type cyclin activity in cells could prevent or cure diabetes.
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Cyclins d2 and d1 are essential for postnatal pancreatic β cell growth
Molecular and Cellular Biology, 2005Co-Authors: Jake A Kushner, Piotr Sicinski, Ewa Sicinska, Maria A Ciemerych, Lynn M Wartschow, Monica Teta, Simon Y Long, Morris F WhiteAbstract:Regulation of adult beta-cell mass in pancreatic islets is essential to preserve sufficient insulin secretion in order to appropriately regulate glucose homeostasis. In many tissues mitogens influence development by stimulating D-type Cyclins (D1, D2, or D3) and activating cyclin-dependent kinases (CDK4 or CDK6), which results in progression through the G(1) phase of the cell cycle. Here we show that Cyclins D2 and D1 are essential for normal postnatal islet growth. In adult murine islets basal cyclin D2 mRNA expression was easily detected, while cyclin D1 was expressed at lower levels and cyclin D3 was nearly undetectable. Prenatal islet development occurred normally in cyclin D2(-/-) or cyclin D1(+/-) D2(-/-) mice. However, beta-cell proliferation, adult mass, and glucose tolerance were decreased in adult cyclin D2(-/-) mice, causing glucose intolerance that progressed to diabetes by 12 months of age. Although cyclin D1(+/-) mice never developed diabetes, life-threatening diabetes developed in 3-month-old cyclin D1(-/+) D2(-/-) mice as beta-cell mass decreased after birth. Thus, Cyclins D2 and D1 were essential for beta-cell expansion in adult mice. Strategies to tightly regulate D-type cyclin activity in beta cells could prevent or cure diabetes.
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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.
Ewa Sicinska - One of the best experts on this subject based on the ideXlab platform.
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kinase independent function of e type Cyclins in liver cancer
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Yan Geng, Wojciech Michowski, Joel M Chick, Yaoyu E Wang, Emmanuelle M Jecrois, Katharine E Sweeney, Lijun Liu, Richard C Han, Agnieszka Zagozdzon, Ewa SicinskaAbstract:E-type Cyclins (Cyclins E1 and E2) are components of the core cell cycle machinery and are overexpressed in many human tumor types. E Cyclins are thought to drive tumor cell proliferation by activating the cyclin-dependent kinase 2 (CDK2). The cyclin E1 gene represents the site of recurrent integration of the hepatitis B virus in the pathogenesis of hepatocellular carcinoma, and this event is associated with strong up-regulation of cyclin E1 expression. Regardless of the underlying mechanism of tumorigenesis, the majority of liver cancers overexpress E-type Cyclins. Here we used conditional cyclin E knockout mice and a liver cancer model to test the requirement for the function of E Cyclins in liver tumorigenesis. We show that a ubiquitous, global shutdown of E Cyclins did not visibly affect postnatal development or physiology of adult mice. However, an acute ablation of E Cyclins halted liver cancer progression. We demonstrated that also human liver cancer cells critically depend on E Cyclins for proliferation. In contrast, we found that the function of the cyclin E catalytic partner, CDK2, is dispensable in liver cancer cells. We observed that E Cyclins drive proliferation of tumor cells in a CDK2- and kinase-independent mechanism. Our study suggests that compounds which degrade or inhibit cyclin E might represent a highly selective therapeutic strategy for patients with liver cancer, as these compounds would selectively cripple proliferation of tumor cells, while sparing normal tissues.
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Cyclins d2 and d1 are essential for postnatal pancreatic β cell growth
Molecular and Cellular Biology, 2005Co-Authors: Piotr Sicinski, Ewa Sicinska, Maria A Ciemerych, Jake A Kushner, Lynn M Wartschow, Monica Teta, Simon Y Long, Morris F WhiteAbstract:Regulation of adult -cell mass in pancreatic islets is essential to preserve sufficient insulin secretion in order to appropriately regulate glucose homeostasis. In many tissues mitogens influence development by stimulating D-type Cyclins (D1, D2, or D3) and activating cyclin-dependent kinases (CDK4 or CDK6), which results in progression through the G1 phase of the cell cycle. Here we show that Cyclins D2 and D1 are essential for normal postnatal islet growth. In adult murine islets basal cyclin D2 mRNA expression was easily detected, while cyclin D1 was expressed at lower levels and cyclin D3 was nearly undetectable. Prenatal islet development occurred normally in cyclin D2 / or cyclin D1 / D2 / mice. However, -cell proliferation, adult mass, and glucose tolerance were decreased in adult cyclin D2 / mice, causing glucose intolerance that progressed to diabetes by 12 months of age. Although cyclin D1 / mice never developed diabetes, life-threatening diabetes developed in 3-month-old cyclin D1 / D2 / mice as -cell mass decreased after birth. Thus, Cyclins D2 and D1 were essential for -cell expansion in adult mice. Strategies to tightly regulate D-type cyclin activity in cells could prevent or cure diabetes.
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Cyclins d2 and d1 are essential for postnatal pancreatic β cell growth
Molecular and Cellular Biology, 2005Co-Authors: Jake A Kushner, Piotr Sicinski, Ewa Sicinska, Maria A Ciemerych, Lynn M Wartschow, Monica Teta, Simon Y Long, Morris F WhiteAbstract:Regulation of adult beta-cell mass in pancreatic islets is essential to preserve sufficient insulin secretion in order to appropriately regulate glucose homeostasis. In many tissues mitogens influence development by stimulating D-type Cyclins (D1, D2, or D3) and activating cyclin-dependent kinases (CDK4 or CDK6), which results in progression through the G(1) phase of the cell cycle. Here we show that Cyclins D2 and D1 are essential for normal postnatal islet growth. In adult murine islets basal cyclin D2 mRNA expression was easily detected, while cyclin D1 was expressed at lower levels and cyclin D3 was nearly undetectable. Prenatal islet development occurred normally in cyclin D2(-/-) or cyclin D1(+/-) D2(-/-) mice. However, beta-cell proliferation, adult mass, and glucose tolerance were decreased in adult cyclin D2(-/-) mice, causing glucose intolerance that progressed to diabetes by 12 months of age. Although cyclin D1(+/-) mice never developed diabetes, life-threatening diabetes developed in 3-month-old cyclin D1(-/+) D2(-/-) mice as beta-cell mass decreased after birth. Thus, Cyclins D2 and D1 were essential for beta-cell expansion in adult mice. Strategies to tightly regulate D-type cyclin activity in beta cells could prevent or cure diabetes.
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mouse development and cell proliferation in the absence of d Cyclins
Cell, 2004Co-Authors: Katarzyna Kozar, Shoumo Bhattacharya, Ewa Sicinska, Yan Geng, Maria A Ciemerych, Agnieszka Zagozdzon, Vivienne I Rebel, Hirokazu Shigematsu, Roderick T BronsonAbstract:D-type Cyclins (Cyclins D1, D2, and D3) are regarded as essential links between cell environment and the core cell cycle machinery. We tested the requirement for D-Cyclins in mouse development and in proliferation by generating mice lacking all D-Cyclins. We found that these cyclin D1(-/-)D2(-/-)D3(-/-) mice develop until mid/late gestation and die due to heart abnormalities combined with a severe anemia. Our analyses revealed that the D-Cyclins are critically required for the expansion of hematopoietic stem cells. In contrast, cyclin D-deficient fibroblasts proliferate nearly normally but show increased requirement for mitogenic stimulation in cell cycle re-entry. We found that the proliferation of cyclin D1(-/-)D2(-/-)D3(-/-) cells is resistant to the inhibition by p16(INK4a), but it critically depends on CDK2. Lastly, we found that cells lacking D-Cyclins display reduced susceptibility to the oncogenic transformation. Our results reveal the presence of alternative mechanisms that allow cell cycle progression in a cyclin D-independent fashion.
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requirement for cyclin d3 in lymphocyte development and t cell leukemias
Cancer Cell, 2003Co-Authors: Ewa Sicinska, Qunyan Yu, Yan Geng, Iannis Aifantis, Wojciech Swat, Christine Borowski, Adolfo A Ferrando, Steven D Levin, Harald Von Boehmer, Piotr SicinskiAbstract:Abstract The D-type Cyclins (Cyclins D1, D2, and D3) are components of the core cell cycle machinery in mammalian cells. Cyclin D3 gene is rearranged and the protein is overexpressed in several human lymphoid malignancies. In order to determine the function of cyclin D3 in development and oncogenesis, we generated and analyzed cyclin D3-deficient mice. We found that cyclin D3 −/− animals fail to undergo normal expansion of immature T lymphocytes and show greatly reduced susceptibility to T cell malignancies triggered by specific oncogenic pathways. The requirement for cyclin D3 also operates in human malignancies, as knock-down of cyclin D3 inhibited proliferation of acute lymphoblastic leukemias deriving from immature T lymphocytes. These studies point to cyclin D3 as a potential target for therapeutic intervention in specific human malignancies.
Yan Geng - One of the best experts on this subject based on the ideXlab platform.
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kinase independent function of e type Cyclins in liver cancer
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Yan Geng, Wojciech Michowski, Joel M Chick, Yaoyu E Wang, Emmanuelle M Jecrois, Katharine E Sweeney, Lijun Liu, Richard C Han, Agnieszka Zagozdzon, Ewa SicinskaAbstract:E-type Cyclins (Cyclins E1 and E2) are components of the core cell cycle machinery and are overexpressed in many human tumor types. E Cyclins are thought to drive tumor cell proliferation by activating the cyclin-dependent kinase 2 (CDK2). The cyclin E1 gene represents the site of recurrent integration of the hepatitis B virus in the pathogenesis of hepatocellular carcinoma, and this event is associated with strong up-regulation of cyclin E1 expression. Regardless of the underlying mechanism of tumorigenesis, the majority of liver cancers overexpress E-type Cyclins. Here we used conditional cyclin E knockout mice and a liver cancer model to test the requirement for the function of E Cyclins in liver tumorigenesis. We show that a ubiquitous, global shutdown of E Cyclins did not visibly affect postnatal development or physiology of adult mice. However, an acute ablation of E Cyclins halted liver cancer progression. We demonstrated that also human liver cancer cells critically depend on E Cyclins for proliferation. In contrast, we found that the function of the cyclin E catalytic partner, CDK2, is dispensable in liver cancer cells. We observed that E Cyclins drive proliferation of tumor cells in a CDK2- and kinase-independent mechanism. Our study suggests that compounds which degrade or inhibit cyclin E might represent a highly selective therapeutic strategy for patients with liver cancer, as these compounds would selectively cripple proliferation of tumor cells, while sparing normal tissues.
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g1 Cyclins link proliferation pluripotency and differentiation of embryonic stem cells
Nature Cell Biology, 2017Co-Authors: Lijun Liu, Yan Geng, Wojciech Michowski, Joel M Chick, Hiroyuki Inuzuka, Kouhei Shimizu, Naoe Taira Nihira, Alice Y Meng, Alban Ordureau, Aleksandra A KolodziejczykAbstract:Progression of mammalian cells through the G1 and S phases of the cell cycle is driven by the D-type and E-type Cyclins. According to the current models, at least one of these cyclin families must be present to allow cell proliferation. Here, we show that several cell types can proliferate in the absence of all G1 Cyclins. However, following ablation of G1 Cyclins, embryonic stem (ES) cells attenuated their pluripotent characteristics, with the majority of cells acquiring the trophectodermal cell fate. We established that G1 Cyclins, together with their associated cyclin-dependent kinases (CDKs), phosphorylate and stabilize the core pluripotency factors Nanog, Sox2 and Oct4. Treatment of murine ES cells, patient-derived glioblastoma tumour-initiating cells, or triple-negative breast cancer cells with a CDK inhibitor strongly decreased Sox2 and Oct4 levels. Our findings suggest that CDK inhibition might represent an attractive therapeutic strategy by targeting glioblastoma tumour-initiating cells, which depend on Sox2 to maintain their tumorigenic potential. Liu et al. show that G1 Cyclins and their cyclin-dependent kinases regulate the pluripotent state by driving phosphorylation of Nanog, Oct4 and Sox2, thereby identifying a direct connection between G1 Cyclins and pluripotency factors.
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differences in regulation and function of e Cyclins in human cancer cells
Cell Cycle, 2013Co-Authors: Yan Geng, Piotr SicinskiAbstract:Mammalian cyclin E was cloned by groups of James Roberts and Steven Reed in a screen for human cDNAs which can complement mutant G1 cyclin genes CLN1, CLN2 and CLN3 in yeast Sacaromyces cerevisiae.1 The flurry of studies which followed this discovery demonstrated that in mammalian cells cyclin E is induced in late G1 phase when it activates cyclin-dependent kinase CDK2, and also CDK1 and CDK3. During G1 phase progression cyclin E-CDK2 kinase phosphorylates and inactivates the retinoblastoma protein, pRB, leading to activation of E2F transcription factors. Since the cyclin E gene represents one of E2F transcriptional targets, this mechanism creates a positive feedback loop which leads to full activation of cyclin E-CDK2 kinase. Once induced, cyclin E-CDK2 phosphorylates proteins governing cell cycle progression (pRB, p27Kip1, E2F5), centrosome duplication (NPM, CP110), histone gene transcription (NPAT) and others. Cyclin E and cyclin E-CDK2 kinase activity is essential for assembly of DNA pre-replication complexes and for firing of DNA replication origins. As the S phase progresses, cyclin E becomes phosphorylated by cyclin E-CDK2 and by GSK3, and is then targeted for proteosomal degradation by the SCFFbw7 ubiquitin ligase.1 Subsequently, groups of Bruno Amati, Yue Xiong and Steve Coats isolated the second mammalian E-type cyclin, which was termed cyclin E2, while the protein known as “cyclin E” was renamed as cyclin E1. The two E-Cyclins show substantial aminoacid similarity, associate with the same CDK partners, and appear to perform similar biological functions.1 Their regulation seems to be similar, including transcriptional activation by E2F and protein degradation through SCFFbw7 ubiquitin ligase. Also in vivo, the two E-type Cyclins seem to perform highly overlapping set of functions. Thus, genetic ablation of Cyclins E1 or E2 resulted in no major phenotypes, whereas combined loss of both E-Cyclins led to an early embryonic lethality due to placental abnormalities.2 In adult mice, combined ablation of Cyclins E1 and E2 impairs neuronal synaptic function and leads to memory deficits, due to a function of cyclin E in regulating synaptic plasticity.3 Collectively, all these observations suggested that Cyclins E1 and E2 are functionally equivalent. A recent study from Elizabeth Musgrove group4 indicates that this prevailing view may need revisions. The authors focused on the function of overexpressed cyclin E in breast cancer cells. Cyclins E1 and E2 are overexpressed in a substantial number of human cancers, where they contribute to tumorigenesis likely by driving uncontrolled cell cycle progression.1 Moreover, overexpression of cyclin E1 was shown to result in chromosome instability in in vitro cultured cells, and in vivo, in mouse tumors.5,6 While the exact molecular mechanism remains to be elucidated, this role of cyclin E1 is mediated, at least in part, by binding and phosphorylating the anaphase-promoting complex (APC) regulatory subunit, Cdh1.7 This, in turn inhibits APC activity, and results in impaired mitotic progression of cyclin E1-overexpressing cells.7 Unexpectedly, Caldon et al.4 now demonstrate that cyclin E2, when overexpressed, does not interact with Cdh1, does not inhibit APC and does not impair mitotic progression. Yet, cyclin E2 overexpression still triggers genomic instability, as evidenced by increased fraction of abnormal mitoses, as well as the presence of chromosomal aberrations such as chromosome breaks and end-to-end fusions in cyclin E2-overexpressing cells. While the mechanism through which cyclin E2 causes these abnormalities remains unclear, Caldon et al.4 propose that this effect is mediated through inactivation of pRB and pRB-like p107 and p130 proteins by hyperactive cyclin E2-CDK2. Intriguingly, the same group demonstrated that the levels of cyclin E2 in cancer cells are controlled via a distinct mechanism from that operating in normal cells.8 Specifically, while in non-transformed cells the levels of Cyclins E1 and E2 are regulated by SCFFbw7, in a breast cancer cells depletion of Fbw7 affects the levels of cyclin E1, but not E2.8 These finding lead to several questions. Are results of Caldon et al.4,8 generalizable across different types of human cancers? How is the stability of cyclin E2 controlled in cancer cells, and how mechanistically cyclin E2 expression shifts from Fbw7-dependent to -independent mode? How does cyclin E2 trigger chromosomal instability? Analyses of the endogenous protein complexes associated with Cyclins E1 and E2 in cancer cells may help to unravel molecular differences between these two related, but apparently distinct proteins.
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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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mouse development and cell proliferation in the absence of d Cyclins
Cell, 2004Co-Authors: Katarzyna Kozar, Shoumo Bhattacharya, Ewa Sicinska, Yan Geng, Maria A Ciemerych, Agnieszka Zagozdzon, Vivienne I Rebel, Hirokazu Shigematsu, Roderick T BronsonAbstract:D-type Cyclins (Cyclins D1, D2, and D3) are regarded as essential links between cell environment and the core cell cycle machinery. We tested the requirement for D-Cyclins in mouse development and in proliferation by generating mice lacking all D-Cyclins. We found that these cyclin D1(-/-)D2(-/-)D3(-/-) mice develop until mid/late gestation and die due to heart abnormalities combined with a severe anemia. Our analyses revealed that the D-Cyclins are critically required for the expansion of hematopoietic stem cells. In contrast, cyclin D-deficient fibroblasts proliferate nearly normally but show increased requirement for mitogenic stimulation in cell cycle re-entry. We found that the proliferation of cyclin D1(-/-)D2(-/-)D3(-/-) cells is resistant to the inhibition by p16(INK4a), but it critically depends on CDK2. Lastly, we found that cells lacking D-Cyclins display reduced susceptibility to the oncogenic transformation. Our results reveal the presence of alternative mechanisms that allow cell cycle progression in a cyclin D-independent fashion.
Jake A Kushner - One of the best experts on this subject based on the ideXlab platform.
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Cyclins d2 and d1 are essential for postnatal pancreatic β cell growth
Molecular and Cellular Biology, 2005Co-Authors: Piotr Sicinski, Ewa Sicinska, Maria A Ciemerych, Jake A Kushner, Lynn M Wartschow, Monica Teta, Simon Y Long, Morris F WhiteAbstract:Regulation of adult -cell mass in pancreatic islets is essential to preserve sufficient insulin secretion in order to appropriately regulate glucose homeostasis. In many tissues mitogens influence development by stimulating D-type Cyclins (D1, D2, or D3) and activating cyclin-dependent kinases (CDK4 or CDK6), which results in progression through the G1 phase of the cell cycle. Here we show that Cyclins D2 and D1 are essential for normal postnatal islet growth. In adult murine islets basal cyclin D2 mRNA expression was easily detected, while cyclin D1 was expressed at lower levels and cyclin D3 was nearly undetectable. Prenatal islet development occurred normally in cyclin D2 / or cyclin D1 / D2 / mice. However, -cell proliferation, adult mass, and glucose tolerance were decreased in adult cyclin D2 / mice, causing glucose intolerance that progressed to diabetes by 12 months of age. Although cyclin D1 / mice never developed diabetes, life-threatening diabetes developed in 3-month-old cyclin D1 / D2 / mice as -cell mass decreased after birth. Thus, Cyclins D2 and D1 were essential for -cell expansion in adult mice. Strategies to tightly regulate D-type cyclin activity in cells could prevent or cure diabetes.
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Cyclins d2 and d1 are essential for postnatal pancreatic β cell growth
Molecular and Cellular Biology, 2005Co-Authors: Jake A Kushner, Piotr Sicinski, Ewa Sicinska, Maria A Ciemerych, Lynn M Wartschow, Monica Teta, Simon Y Long, Morris F WhiteAbstract:Regulation of adult beta-cell mass in pancreatic islets is essential to preserve sufficient insulin secretion in order to appropriately regulate glucose homeostasis. In many tissues mitogens influence development by stimulating D-type Cyclins (D1, D2, or D3) and activating cyclin-dependent kinases (CDK4 or CDK6), which results in progression through the G(1) phase of the cell cycle. Here we show that Cyclins D2 and D1 are essential for normal postnatal islet growth. In adult murine islets basal cyclin D2 mRNA expression was easily detected, while cyclin D1 was expressed at lower levels and cyclin D3 was nearly undetectable. Prenatal islet development occurred normally in cyclin D2(-/-) or cyclin D1(+/-) D2(-/-) mice. However, beta-cell proliferation, adult mass, and glucose tolerance were decreased in adult cyclin D2(-/-) mice, causing glucose intolerance that progressed to diabetes by 12 months of age. Although cyclin D1(+/-) mice never developed diabetes, life-threatening diabetes developed in 3-month-old cyclin D1(-/+) D2(-/-) mice as beta-cell mass decreased after birth. Thus, Cyclins D2 and D1 were essential for beta-cell expansion in adult mice. Strategies to tightly regulate D-type cyclin activity in beta cells could prevent or cure diabetes.
Morris F White - One of the best experts on this subject based on the ideXlab platform.
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Cyclins d2 and d1 are essential for postnatal pancreatic β cell growth
Molecular and Cellular Biology, 2005Co-Authors: Piotr Sicinski, Ewa Sicinska, Maria A Ciemerych, Jake A Kushner, Lynn M Wartschow, Monica Teta, Simon Y Long, Morris F WhiteAbstract:Regulation of adult -cell mass in pancreatic islets is essential to preserve sufficient insulin secretion in order to appropriately regulate glucose homeostasis. In many tissues mitogens influence development by stimulating D-type Cyclins (D1, D2, or D3) and activating cyclin-dependent kinases (CDK4 or CDK6), which results in progression through the G1 phase of the cell cycle. Here we show that Cyclins D2 and D1 are essential for normal postnatal islet growth. In adult murine islets basal cyclin D2 mRNA expression was easily detected, while cyclin D1 was expressed at lower levels and cyclin D3 was nearly undetectable. Prenatal islet development occurred normally in cyclin D2 / or cyclin D1 / D2 / mice. However, -cell proliferation, adult mass, and glucose tolerance were decreased in adult cyclin D2 / mice, causing glucose intolerance that progressed to diabetes by 12 months of age. Although cyclin D1 / mice never developed diabetes, life-threatening diabetes developed in 3-month-old cyclin D1 / D2 / mice as -cell mass decreased after birth. Thus, Cyclins D2 and D1 were essential for -cell expansion in adult mice. Strategies to tightly regulate D-type cyclin activity in cells could prevent or cure diabetes.
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Cyclins d2 and d1 are essential for postnatal pancreatic β cell growth
Molecular and Cellular Biology, 2005Co-Authors: Jake A Kushner, Piotr Sicinski, Ewa Sicinska, Maria A Ciemerych, Lynn M Wartschow, Monica Teta, Simon Y Long, Morris F WhiteAbstract:Regulation of adult beta-cell mass in pancreatic islets is essential to preserve sufficient insulin secretion in order to appropriately regulate glucose homeostasis. In many tissues mitogens influence development by stimulating D-type Cyclins (D1, D2, or D3) and activating cyclin-dependent kinases (CDK4 or CDK6), which results in progression through the G(1) phase of the cell cycle. Here we show that Cyclins D2 and D1 are essential for normal postnatal islet growth. In adult murine islets basal cyclin D2 mRNA expression was easily detected, while cyclin D1 was expressed at lower levels and cyclin D3 was nearly undetectable. Prenatal islet development occurred normally in cyclin D2(-/-) or cyclin D1(+/-) D2(-/-) mice. However, beta-cell proliferation, adult mass, and glucose tolerance were decreased in adult cyclin D2(-/-) mice, causing glucose intolerance that progressed to diabetes by 12 months of age. Although cyclin D1(+/-) mice never developed diabetes, life-threatening diabetes developed in 3-month-old cyclin D1(-/+) D2(-/-) mice as beta-cell mass decreased after birth. Thus, Cyclins D2 and D1 were essential for beta-cell expansion in adult mice. Strategies to tightly regulate D-type cyclin activity in beta cells could prevent or cure diabetes.
