The Experts below are selected from a list of 283704 Experts worldwide ranked by ideXlab platform
Amit Verma - One of the best experts on this subject based on the ideXlab platform.
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macrocytosis and dysplastic anemia is associated with the cyclin dependent Kinase 4 6 inhibitor palbociclib in metastatic breast cancer
Haematologica, 2017Co-Authors: Jesus Anampa, Tamanna Haque, Irina Murakhovskaya, Yanhua Wang, Kimo Bachiashvili, Cristian Papazoglu, Kith Pradhan, Ulrich Steidl, Joseph A Sparano, Amit VermaAbstract:Palbociclib is a Cyclin-Dependent Kinase (CDK) inhibitor of CDK4 and CDK6 that has been approved by the US Food and Drug Administration (FDA) for the treatment of estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC), demonstrating an improvement in progression-free survival
Joan Massagué - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of the p27kip1 cyclin dependent Kinase inhibitor bound to the cyclin a cdk2 complex
Nature, 1996Co-Authors: Alicia A Russo, Joan Massagué, Philip D Jeffrey, Andrea K Patten, Nikola P PavletichAbstract:The crystal structure of the human p27Kip1 Kinase inhibitory domain bound to the phosphorylated cyclin A–Cyclin-Dependent Kinase 2 (Cdk2) complex has been determined at 2.3 A. p27Kip1 binds the complex as an extended structure interacting with both cyclin A and Cdk2. On cyclin A, it binds in a groove formed by conserved cyclin box residues. On Cdk2, it binds and rearranges the amino-terminal lobe and also inserts into the catalytic cleft, mimicking ATP.
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interleukin 2 mediated elimination of the p27kip1 cyclin dependent Kinase inhibitor prevented by rapamycin
Nature, 1994Co-Authors: Jamison Nourse, Eduardo Firpo, Michael W Flanagan, Steve Coats, Joan Massagué, Kornelia Polyak, Gerald R Crabtree, James M RobertsAbstract:THE Cyclin-Dependent Kinase (Cdk) enzymes, when associated with the G1 cyclins D and E, are rate-limiting for entry into the S phase of the cell cycle1,2. During T-cell mitogenesis, antigen–receptor signalling promotes synthesis of cyclin E and its catalytic partner, Cdk2, and interleukin-2 (IL-2) signalling activates cyclin E/Cdk2 complexes3. Rapamycin is a potent immunosuppressant which specifically inhibits Gl-to-S-phase progression, leading to cell-cycle arrest in yeast and mammals4–7. Here we report that IL-2 allows Cdk activation by causing the elimination of the Cdk inhibitor protein p27Kip1, and that this is prevented by rapamycin. By contrast, the Cdk inhibitor p21 is induced by IL-2 and this induction is blocked by rapamycin. Our results show that p27Kiplgoverns Cdk activity during the transition from quiescence to S phase in T lymphocytes and that p21 function may be restricted to cycling cells.
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cyclic amp induced g1 phase arrest mediated by an inhibitor p27kip1 of cyclin dependent Kinase 4 activation
Cell, 1994Co-Authors: Junya Kato, Joan Massagué, Kornelia Polyak, Masaaki Matsuoka, Charles J SherrAbstract:Abstract Cyclic AMP (cAMP) blocks the mitogenic effects of colony-stimulating factor 1 (CSF-1) in macrophages, inducing cell cycle arrest in mid-G1 phase. Complexes between cyclin D1 and Cyclin-Dependent Kinase 4 (cdk4) assemble in growth arrested cells, but cdk4 is not phosphorylated in vivo by the cdk-activating Kinase (CAK) and remains inactive. Although undetectable in lysates of cAMP-treated cells, active CAK is recovered after antibody precipitation, indicating that it is not the direct target of inhibition. Levels of the cdk inhibitor p27 Kip1 increase in cAMP-treated cells, and its immunodepletion from inhibitory lysates restores CAK-mediated cdk4 activation. Kip1 does not bind to CAK, but its association with cyclin D-cdk4 prevents CAK from phosphorylating and activating the holoenzyme.
Dennis A Carson - One of the best experts on this subject based on the ideXlab platform.
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expression of the p16 and p15 cyclin dependent Kinase inhibitors in lymphocyte activation and neuronal differentiation
Cancer Research, 1995Co-Authors: Augusto F Lois, Tsutomu Nobori, Leslie T Cooper, Yu Geng, Dennis A CarsonAbstract:The Cyclin-Dependent Kinase inhibitors p16INK4/MTS1 and p15INK4B/MTS2 have been mapped to a region in chromosome 9 (921) that is deleted frequently in acute lymphoblastic leukemias and malignant gliomas. To gain insight into the functions of these inhibitors in lymphocytes and neuronal cells, we studied the expression of p15 and p16 during lymphocyte mitogenesis and neuronal differentiation. Expression of p15 was extinguished during lymphocyte activation, concomitant with an increase in retinoblastoma Kinase activity. The differentiation of the embryonic teratocarcinoma cell line NT2 into postmitotic neurons (hNT) was associated with enhanced expression of p15 and p16 proteins. These findings suggest that p15 and p16 play a role in maintaining cell quiescence in lymphocytes and neuronal cells, respectively. Deletions of these genes may thus promote unrestrained growth.
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deletions of the cyclin dependent Kinase 4 inhibitor gene in multiple human cancers
Nature, 1994Co-Authors: Tsutomu Nobori, Kaoru Miura, David J Wu, Augusto F Lois, Kenji Takabayashi, Dennis A CarsonAbstract:CYTOGENETIC abnormalities of chromosome 9p21 are characteristic of malignant melanomas1,2, gliomas3, lung cancers4 and leukaemias5. From a panel of 46 human malignant cell lines, we localized by positional cloning the most frequently deleted region on 9p21. Sequence analysis of the isolated fragment reveals two open reading frames identical to the recently described complementary DNA for the inhibitor of Cyclin-Dependent Kinase 4 (CDK4) 6. Polymerase chain reaction and Southern blot analysis confirmed the frequent deletion or rearrangement of the CDK4-inhibitor gene in melanomas, gliomas, lung cancers and leukaemias, and the absence of detectable gene transcripts. One carcinoma had a deletion entirely within the CDK4-inhibitor gene. The CDK4-inhibitor gene from a patient with dysplastic nevus syndrome had a germ-line nonsense mutation. The CDK4 inhibitor is thought to be a physiological suppressor of proliferation. Cells unable to produce the inhibitor may be prone to neoplastic transformation.
Kornelia Polyak - One of the best experts on this subject based on the ideXlab platform.
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interleukin 2 mediated elimination of the p27kip1 cyclin dependent Kinase inhibitor prevented by rapamycin
Nature, 1994Co-Authors: Jamison Nourse, Eduardo Firpo, Michael W Flanagan, Steve Coats, Joan Massagué, Kornelia Polyak, Gerald R Crabtree, James M RobertsAbstract:THE Cyclin-Dependent Kinase (Cdk) enzymes, when associated with the G1 cyclins D and E, are rate-limiting for entry into the S phase of the cell cycle1,2. During T-cell mitogenesis, antigen–receptor signalling promotes synthesis of cyclin E and its catalytic partner, Cdk2, and interleukin-2 (IL-2) signalling activates cyclin E/Cdk2 complexes3. Rapamycin is a potent immunosuppressant which specifically inhibits Gl-to-S-phase progression, leading to cell-cycle arrest in yeast and mammals4–7. Here we report that IL-2 allows Cdk activation by causing the elimination of the Cdk inhibitor protein p27Kip1, and that this is prevented by rapamycin. By contrast, the Cdk inhibitor p21 is induced by IL-2 and this induction is blocked by rapamycin. Our results show that p27Kiplgoverns Cdk activity during the transition from quiescence to S phase in T lymphocytes and that p21 function may be restricted to cycling cells.
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cyclic amp induced g1 phase arrest mediated by an inhibitor p27kip1 of cyclin dependent Kinase 4 activation
Cell, 1994Co-Authors: Junya Kato, Joan Massagué, Kornelia Polyak, Masaaki Matsuoka, Charles J SherrAbstract:Abstract Cyclic AMP (cAMP) blocks the mitogenic effects of colony-stimulating factor 1 (CSF-1) in macrophages, inducing cell cycle arrest in mid-G1 phase. Complexes between cyclin D1 and Cyclin-Dependent Kinase 4 (cdk4) assemble in growth arrested cells, but cdk4 is not phosphorylated in vivo by the cdk-activating Kinase (CAK) and remains inactive. Although undetectable in lysates of cAMP-treated cells, active CAK is recovered after antibody precipitation, indicating that it is not the direct target of inhibition. Levels of the cdk inhibitor p27 Kip1 increase in cAMP-treated cells, and its immunodepletion from inhibitory lysates restores CAK-mediated cdk4 activation. Kip1 does not bind to CAK, but its association with cyclin D-cdk4 prevents CAK from phosphorylating and activating the holoenzyme.
Charles J Sherr - One of the best experts on this subject based on the ideXlab platform.
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cyclic amp induced g1 phase arrest mediated by an inhibitor p27kip1 of cyclin dependent Kinase 4 activation
Cell, 1994Co-Authors: Junya Kato, Joan Massagué, Kornelia Polyak, Masaaki Matsuoka, Charles J SherrAbstract:Abstract Cyclic AMP (cAMP) blocks the mitogenic effects of colony-stimulating factor 1 (CSF-1) in macrophages, inducing cell cycle arrest in mid-G1 phase. Complexes between cyclin D1 and Cyclin-Dependent Kinase 4 (cdk4) assemble in growth arrested cells, but cdk4 is not phosphorylated in vivo by the cdk-activating Kinase (CAK) and remains inactive. Although undetectable in lysates of cAMP-treated cells, active CAK is recovered after antibody precipitation, indicating that it is not the direct target of inhibition. Levels of the cdk inhibitor p27 Kip1 increase in cAMP-treated cells, and its immunodepletion from inhibitory lysates restores CAK-mediated cdk4 activation. Kip1 does not bind to CAK, but its association with cyclin D-cdk4 prevents CAK from phosphorylating and activating the holoenzyme.
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d type cyclin dependent Kinase activity in mammalian cells
Molecular and Cellular Biology, 1994Co-Authors: Hitoshi Matsushime, Dawn E Quelle, Sheila A. Shurtleff, Charles J Sherr, Masabumi Shibuya, Junya KatoAbstract:Abstract D-type Cyclin-Dependent Kinase activities have not so far been detected in mammalian cells. Lysis of rodent fibroblasts, mouse macrophages, or myeloid cells with Tween 20 followed by precipitation with antibodies to cyclins D1, D2, and D3 or to their major catalytic partner, Cyclin-Dependent Kinase 4 (cdk4), yielded Kinase activities in immune complexes which readily phosphorylated the retinoblastoma protein (pRb) but not histone H1 or casein. Virtually all cyclin D1-dependent Kinase activity in proliferating macrophages and fibroblasts could be attributed to cdk4. When quiescent cells were stimulated by growth factors to enter the cell cycle, cyclin D1-dependent Kinase activity was first detected in mid G1, reached a maximum near the G1/S transition, and remained elevated in proliferating cells. The rate of appearance of Kinase activity during G1 phase lagged significantly behind cyclin induction and correlated with the more delayed accumulation of cdk4 and formation of cyclin D1-cdk4 complexes. Thus, cyclin D1-associated Kinase activity was not detected during the G0-to-G1 transition, which occurs within the first few hours following growth factor stimulation. Rodent fibroblasts engineered to constitutively overexpress either cyclin D1 alone or cyclin D3 together with cdk4 exhibited greatly elevated cyclin D-dependent Kinase activity, which remained absent in quiescent cells but rose to supraphysiologic levels as cells progressed through G1. Therefore, despite continued enforced overproduction of cyclins and cdk4, the assembly of cyclin D-cdk4 complexes and the appearance of their Kinase activities remained dependent upon serum stimulation, indicating that upstream regulators must govern formation of the active enzymes.
