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Pierre P. Roger - One of the best experts on this subject based on the ideXlab platform.
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the cdk4 cdk6 inhibitor pd0332991 paradoxically stabilizes activated Cyclin D3 cdk4 6 complexes
Cell Cycle, 2014Co-Authors: Sabine Paternot, Bianca Colleoni, Xavier Bisteau, Pierre P. RogerAbstract:CDK4 and CDK6 bound to D-type Cyclins are master integrators of G1 phase cell cycle regulations by initiating the inactivating phosphorylation of the central oncosuppressor pRb. Because of their frequent deregulation in cancer, Cyclin D-CDK4/6 complexes are emerging as especially promising therapeutic targets. The specific CDK4/6 inhibitor PD0332991 is currently tested in a growing number of phase II/III clinical trials against a variety of pRb-proficient chemotherapy-resistant cancers. We have previously shown that PD0332991 inhibits not only CDK4/6 activity but also the activation by phosphorylation of the bulk of Cyclin D-CDK4 complexes stabilized by p21 binding. Here we show that PD0332991 has either a positive or a negative impact on the activation of Cyclin D-CDK4/6 complexes, depending on their binding to p21. Indeed, whereas PD0332991 inhibits the phosphorylation and activity of p21-bound CDK4/6, it specifically stabilized activated Cyclin D3-CDK4/6 complexes devoid of p21 and p27. After elimination of PD0332991, these activated Cyclin D3-CDK4/6 complexes persisted for at least 24 h, resulting in paradoxical cell cycle entry in the absence of a mitogenic stimulation. This unsuspected positive effect of PD0332991 on Cyclin D3-CDK4/6 activation should be carefully assessed in the clinical evaluation of PD0332991, which until now only involves discontinuous administration protocols.
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Cyclic AMP-dependent Phosphorylation of Cyclin D3-bound CDK4 Determines the Passage through the Cell Cycle Restriction Point in Thyroid Epithelial Cells
The Journal of biological chemistry, 2003Co-Authors: Sabine Paternot, Katia Coulonval, Jacques Emile Dumont, Pierre P. RogerAbstract:According to current concepts, the cell cycle commitment after restriction (R) point passage requires the sustained stimulation by mitogens of the synthesis of labile d-type Cyclins, which associate with Cyclin-dependent kinase (CDK) 4/6 to phosphorylate pRb family proteins and sequester the CDK inhibitor p27kip1. In primary cultures of dog thyroid epithelial cells, the cAMP-dependent cell cycle induced by a sustained stimulation by thyrotropin or forskolin differs from growth factor mitogenic pathways, as cAMP does not upregulate d-type Cyclins but increases p27 levels. Instead, cAMP induces the assembly of required Cyclin D3-CDK4 complexes, which associate with nuclear p27. In this study, the arrest of forskolin stimulation rapidly slowed down the entry of dog thyrocytes into S phase and the phosphorylation of pRb family proteins. The pRb kinase activity, but not the formation, of the Cyclin D3-CDK4-p27 complex was strongly reduced. Using two-dimensional gel electrophoresis, a phosphorylated form of CDK4 was separated. It appeared in response to forskolin and was bound to both Cyclin D3 and p27, presumably reflecting the activating Thr-172 phosphorylation of CDK4. Upon forskolin withdrawal or after cycloheximide addition, this CDK4 phosphoform unexpectedly persisted in p27 complexes devoid of Cyclin D3 but it disappeared from the more labile Cyclin D3 complexes. These data demonstrate that the assembly of the Cyclin D3-CDK4-p27 holoenzyme and the subsequent phosphorylation and activation of CDK4 depend on distinct cAMP actions. This provides a first example of a crucial regulation of CDK4 phosphorylation by a mitogenic cascade and a novel mechanism of cell cycle control at the R point.
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transforming growth factor beta 1 selectively inhibits the cyclic amp dependent proliferation of primary thyroid epithelial cells by preventing the association of Cyclin D3 cdk4 with nuclear p27 kip1
Molecular Biology of the Cell, 2000Co-Authors: Fabienne Depoortere, Jacques Emile Dumont, Jiri Bartek, Isabelle Pirson, Pierre P. RogerAbstract:Dog thyroid epithelial cells in primary culture constitute a physiologically relevant model of positive control of DNA synthesis initiation and G0-S prereplicative phase progression by cAMP as a second messenger for thyrotropin (thyroid-stimulating hormone [TSH]). As previously shown in this system, the cAMP-dependent mitogenic pathway differs from growth factor cascades as it stimulates the accumulation of p27(kip1) but not Cyclins D. Nevertheless, TSH induces the nuclear translocations and assembly of Cyclin D3 and cdk4, which are essential in cAMP-dependent mitogenesis. Here we demonstrate that transforming growth factor beta(1) (TGFbeta(1)) selectively inhibits the cAMP-dependent cell cycle in mid-G1 and various cell cycle regulatory events, but it weakly affects the stimulation of DNA synthesis by epidermal growth factor (EGF), hepatocyte growth factor, serum, and phorbol esters. EGF+serum and TSH did not interfere importantly with TGFbeta receptor signaling, because they did not affect the TGFbeta-induced nuclear translocation of Smad 2 and 3. TGFbeta inhibited the phosphorylation of Rb, p107, and p130 induced by TSH, but it weakly affected the phosphorylation state of Rb-related proteins in EGF+serum-treated cells. TGFbeta did not inhibit c-myc expression. In TSH-stimulated cells, TGFbeta did not affect the expression of Cyclin D3, cdk4, and p27(kip1), nor the induced formation of Cyclin D3-cdk4 complexes, but it prevented the TSH-induced relocalization of p27(kip1) from cdk2 to Cyclin D3-cdk4. It prevented the nuclear translocations of cdk4 and Cyclin D3 without altering the assembly of Cyclin D3-cdk4 complexes probably formed in the cytoplasm, where they were prevented from sequestering nuclear p27(kip1) away from cdk2. This study dissociates the assembly of Cyclin D3-cdk4 complexes from their nuclear localization and association with p27(kip1). It provides a new mechanism of regulation of proliferation by TGFbeta, which points out the subcellular location of Cyclin D-cdk4 complexes as a crucial factor integrating mitogenic and antimitogenic regulations in an epithelial cell in primary culture.
Giuseppe Viale - One of the best experts on this subject based on the ideXlab platform.
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Cyclin D3 immunoreactivity in follicular lymphoma is independent of the t 6 14 p21 1 q32 3 translocation or Cyclin D3 gene amplification and is correlated with histologic grade and ki 67 labeling index
International Journal of Cancer, 2004Co-Authors: Giancarlo Pruneri, Sonia Fabris, Barbara Del Curto, Francesco Bertolini, Giuseppe Viale, Stefano Valentini, Daniele Laszlo, Giovanni Martinelli, P LeocataAbstract:An abnormal expression of Cyclin D3, a key regulator of the cell cycle, has been documented in a variety of human malignancies, and the Cyclin D3 gene, mapping to 6p21, may be deregulated in plasma cell myeloma and non-Hodgkin's lymphoma as a result of the t(6;14)(p21.1;q32.3) translocation and/or gene amplification. In the current study, we for the first time investigated by immunohistochemistry and fluorescence in situ hybridization (FISH) the prevalence of Cyclin D3 abnormalities in follicular lymphomas (FLs), comparing the results with traditional clinicopathologic characteristics, p27 and skp2 immunoreactivity (IR) and Ki-67 labeling index (LI). Cyclin D3, skp2 and Ki-67 IR significantly increased from grade I to grade III FL (p = 0.0003, p = 0.0001 and p < 0.0001, respectively), while p27 IR was significantly (p < 0.0001) more prevalent in low-grade tumors. Cyclin D3 IR was directly correlated with the Ki-67 LI (p < 0.0001) and inversely correlated with p27 IR (p = 0.050). None of the 13 cases analyzed by FISH showed the t(6;14) translocation, but in 2 (15.3%) grade I FLs 3 Cyclin D3 signals were detected. Cohybridization with probes specific for the centromeric region and the long arm of the chromosome 6 indicated trisomy in one case and a pattern highly suggestive for the presence of an isochromosome 6p in the other case. Our data suggest that the t(6;14) translocation may be extremely uncommon in FL and that a deregulated expression of Cyclin D3, possibly due to epigenetic mechanisms, may be involved in the pathogenesis of high-grade tumors.
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Cyclin D3 immunoreactivity in gastrointestinal stromal tumors is independent of Cyclin D3 gene amplification and is associated with nuclear p27 accumulation
Modern Pathology, 2003Co-Authors: Giancarlo Pruneri, Giovanni Mazzarol, Sonia Fabris, Barbara Del Curto, Francesco Bertolini, Antonino Neri, Giuseppe VialeAbstract:Cyclin D3 Immunoreactivity in Gastrointestinal Stromal Tumors Is Independent of Cyclin D3 Gene Amplification and Is Associated with Nuclear p27 Accumulation
Bernard Roizman - One of the best experts on this subject based on the ideXlab platform.
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interwoven roles of Cyclin D3 and cdk4 recruited by icp0 and icp4 in the expression of herpes simplex virus genes
Journal of Virology, 2010Co-Authors: Maria Kalamvoki, Bernard RoizmanAbstract:Elsewhere this laboratory reported that (i) ICP0 interacts with Cyclin D3 but not D1 or D2. The 3 Cyclins independently partially rescue ΔICP0 mutants. (ii) Interaction with Cyclin D3 is required for the switch from nuclear to cytoplasmic accumulation of ICP0. (iii) In infected cells cdk4 is activated whereas cdk2 is not. Inhibition of cdk4 results in nuclear retention of ICP0. Overexpression of Cyclin D3 reverses the effect of the inhibitor. Here we report the following. (i) cdk4 interacts with ICP0, ICP4, and possibly with ICP8. This interaction is required to recruit cdk4 initially to ND10 and later to the viral replication compartments. (ii) cdk4 inhibitor I reduced or delayed the transcription and ultimately translation of mRNAs of ICP4, ICP27, or ICP8 and to a lesser extent that of the ICP0 gene in wild-type virus-infected cells. (iii) Overexpression of Cyclin D3 resulted in a more rapid transcription of these genes. In the presence of inhibitor, the rates of accumulation of the products of these genes resemble those of wild-type virus in the absence of inhibitor. (iv) Overexpression of Cyclin D3 also results in mobilization of cdk6 in nuclei of infected cells. We conclude that ICP0 encodes a function that enhances the recruitment of Cyclin D3 to ND10 structures to activate cdk4 and that ICP0 along with other viral proteins recruits cdk4 to ND10 structures and ultimately to replication compartments for enhanced expression of viral genes and viral DNA synthesis.
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role of Cyclin D3 in the biology of herpes simplex virus 1 icp0
Journal of Virology, 2001Co-Authors: C Van Sant, Pascal Lopez, Sunil J Advani, Bernard RoizmanAbstract:Earlier reports from this laboratory have shown that the promiscuous transactivator infected-cell protein 0 (ICP0) binds and stabilizes Cyclin D3, that the binding site maps to aspartic acid 199 (D199), and that replacement of D199 with alanine abolishes binding and reduces the capacity of the mutant virus to replicate in quiescent cells or to cause mortality in mice infected by a peripheral site. The objective of this report was to investigate the role of Cyclin D3 in the biology of ICP0. We report the following results. (i) Wild-type ICP0 activates Cyclin D-dependent kinase 4 (cdk4) and stabilizes Cyclin D1 although ICP0 does not interact with this Cyclin. (ii) The D199A mutant virus (R7914) does not activate cdk4 or stabilize Cyclin D1, and neither the wild-type nor the mutant virus activates cdk2. (iii) Early in infection of human embryonic lung (HEL) fibroblasts both wild-type and D199A mutant ICP0s colocalize with PML, and in these cells the ND10 nuclear structures are dispersed. Whereas wild-type ICP0 is transported to the cytoplasm between 3 and 9 h. after infection, ICPO containing the D199A substitution remains quantitatively in the nucleus. (iv) To examine the interaction of ICP0 with Cyclin D3, we used a previously described mutant carrying a wild-type ICP0 but expressing Cyclin D3 (R7801) and in addition constructed a virus (R7916) that was identical except that it carried the D199A-substituted ICP0. Early in infection with R7801, ICP0 colocalized with Cyclin D3 in structures similar to those containing PML. At 3 h after infection, ICP0 was translocated to the cytoplasm whereas Cyclin D3 remained in the nucleus. The translocation of ICP0 to the cytoplasm was accelerated in cells expressing Cyclin D3 compared with that of ICP0 expressed by wild-type virus. In contrast, ICP0 carrying the D199A substitution remained in the nucleus and did not colocalize with Cyclin D3. These studies suggest the following conclusions. (i) ICP0 brings to the vicinity of ND10 Cyclin D3 and, in consequence, an activated cdk4. The metabolic events occurring at or near that structure and involving Cyclin D3 cause the translocation of ICP0 to the cytoplasm. (ii) In the absence of the Cyclin D3 binding site in ICP0, Cyclin D3 is not brought to ND10, Cyclin D is not stabilized, and the function responsible for the translocation of ICP0 is not expressed, and in quiescent HEL fibroblasts the yields of virus are reduced.
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herpes simplex virus 1 alpha regulatory protein icp0 interacts with and stabilizes the cell cycle regulator Cyclin D3
Journal of Virology, 1997Co-Authors: Y Kawaguchi, C Van Sant, Bernard RoizmanAbstract:The herpes simplex virus 1 (HSV-1) infected-cell protein 0 (ICP0) has the characteristics of a promiscuous transactivator of genes introduced into cells by infection or transfection. To identify cellular proteins interacting with ICP0, we used a domain of exon II of ICP0 that is known to be crucial for regulatory function of the protein as bait in the yeast two-hybrid screen. Our results were as follows. (i) A cDNA in a positive yeast colony was found to encode Cyclin D3, a cell cycle regulator of G1 phase. (ii) A purified chimeric protein consisting of glutathione S-transferase (GST) fused to Cyclin D3 specifically formed complexes with ICP0 contained in HSV-1-infected cell lysate. (iii) To enhance the expression of Cyclin D3, the gene was inserted into the viral genome and overexpressed in infected cells. The overexpressed Cyclin D3 colocalized with ICP0 in nuclear structures characteristic of ND10 and which earlier have been reported to contain ICP0. (iv) The accumulation of Cyclin D3 protein in Vero cells infected with an alpha0 deletion mutant was reduced relative to that of cells infected with wild-type virus or a recombinant virus in which the deleted alpha0 sequences were restored. (v) Lysates of Spodoptera frugiperda Sf9 cells doubly infected with baculoviruses genetically engineered to express Cyclin D3 and Cyclin-dependent kinase 4 (CDK4) phosphorylated GST fused to retinoblastoma protein (GST-pRb) but did not phosphorylate the GST-alpha0(20-241) or GST-alpha0(543-768) fusion protein or immunoprecipitated ICP0 proteins. Moreover, the chimeric GST-ICP0(exon II) protein shown to bind Cyclin D3 had no effect on the activity of the kinase on GST-pRb when added to mixtures of lysates of Sf9 cells which coexpressed Cyclin D3 and CDK4. These results indicate that ICP0 interacts with, colocalizes with, and stabilizes the Cyclin D3 cell cycle regulator and does not affect its interaction with the Cyclin-dependent kinase.
Anna Maria Billi - One of the best experts on this subject based on the ideXlab platform.
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phospholipase c beta1 pi plcbeta1 Cyclin D3 protein kinase c pkc alpha signaling modulation during iron induced oxidative stress in myelodysplastic syndromes mds
The FASEB Journal, 2020Co-Authors: Alessandra Cappellini, Sara Mongiorgi, Carlo Finelli, Antonietta Fazio, Stefano Ratti, Maria Vittoria Marvi, Antonio Curti, Valentina Salvestrini, Andrea Pellagatti, Anna Maria BilliAbstract:MDS are characterized by anemia and transfusion requirements. Transfused patients frequently show iron overload that negatively affects hematopoiesis. Iron chelation therapy can be effective in these MDS cases, but the molecular consequences of this treatment need to be further investigated. That is why we studied the molecular features of iron effect and Deferasirox therapy on PI-PLCbeta1 inositide signaling, using hematopoietic cells and MDS samples. At baseline, MDS patients showing a positive response after iron chelation therapy displayed higher levels of PI-PLCbeta1/Cyclin D3/PKCalpha expression. During treatment, these responder patients, as well as hematopoietic cells treated with FeCl3 and Deferasirox, showed a specific reduction of PI-PLCbeta1/Cyclin D3/PKCalpha expression, indicating that this signaling pathway is targeted by Deferasirox. The treatment was also able to specifically decrease the production of ROS. This effect correlated with a reduction of IL-1A and IL-2, as well as Akt/mTOR phosphorylation. In contrast, cells exposed only to FeCl3 and cells from MDS patients refractory to Deferasirox showed a specific increase of ROS and PI-PLCbeta1/Cyclin D3/PKCalpha expression. All in all, our data show that PI-PLCbeta1 signaling is a target for iron-induced oxidative stress and suggest that baseline PI-PLCbeta1 quantification could predict iron chelation therapy response in MDS.
Billi, Anna Maria - One of the best experts on this subject based on the ideXlab platform.
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Phospholipase C beta1 (PI-PLCbeta1)/Cyclin D3/protein kinase C (PKC) alpha signaling modulation during iron-induced oxidative stress in myelodysplastic syndromes (MDS)
'FASEB', 2020Co-Authors: Cappellini Alessandra, Mongiorgi Sara, Finelli Carlo, Fazio Antonietta, Ratti Stefano, Marvi, Maria Vittoria, Curti Antonio, Salvestrini Valentina, Pellagatti Andrea, Billi, Anna MariaAbstract:MDS are characterized by anemia and transfusion requirements. Transfused patients frequently show iron overload that negatively affects hematopoiesis. Iron chelation therapy can be effective in these MDS cases, but the molecular consequences of this treatment need to be further investigated. That is why we studied the molecular features of iron effect and Deferasirox therapy on PI-PLCbeta1 inositide signaling, using hematopoietic cells and MDS samples. At baseline, MDS patients showing a positive response after iron chelation therapy displayed higher levels of PI-PLCbeta1/Cyclin D3/PKCalpha expression. During treatment, these responder patients, as well as hematopoietic cells treated with FeCl(3)and Deferasirox, showed a specific reduction of PI-PLCbeta1/Cyclin D3/PKCalpha expression, indicating that this signaling pathway is targeted by Deferasirox. The treatment was also able to specifically decrease the production of ROS. This effect correlated with a reduction of IL-1A and IL-2, as well as Akt/mTOR phosphorylation. In contrast, cells exposed only to FeCl(3)and cells from MDS patients refractory to Deferasirox showed a specific increase of ROS and PI-PLCbeta1/Cyclin D3/PKCalpha expression. All in all, our data show that PI-PLCbeta1 signaling is a target for iron-induced oxidative stress and suggest that baseline PI-PLCbeta1 quantification could predict iron chelation therapy response in MDS
