The Experts below are selected from a list of 196653 Experts worldwide ranked by ideXlab platform
Mamoru Fukuda - One of the best experts on this subject based on the ideXlab platform.
-
in vitro ubiquitination of Cyclin d1 by roc1 cul1 and roc1 cul3
FEBS Letters, 2001Co-Authors: Ichiro Maeda, Tomohiko Ohta, Hirotaka Koizumi, Mamoru FukudaAbstract:Overexpression of Cyclin D1 has been implicated in a variety of tumors, such as breast cancers, gastrointestinal cancers and lymphomas. Both gene amplification and protein degradation mediated by ubiquitin (Ub)-dependent proteolysis regulate the abundance of Cyclin D1. Here we report that ROC1 interacted with all three D type Cyclins in vivo but did not bind to other Cyclins tested. The ROC1–CUL1 and ROC1–CUL3, but not ROC1–CUL2, –CUL3 and –CUL4, immunocomplexes promoted polyubiquitination of bacterially purified Cyclin D1 in vitro. RING finger mutations of ROC1 eliminated the Ub ligase activity toward Cyclin D1. In all cases the ubiquitination of Cyclin D1 was accompanied by autoubiquitination of the cullins. The results suggest the involvement of ROC1–cullin ligases in Cyclin D1 ubiquitination and a potential mechanism whereby the cullin subunit is ubiquitinated itself while ubiquitinating a substrate.
-
In vitro ubiquitination of Cyclin D1 by ROC1–CUL1 and ROC1–CUL3
FEBS Letters, 2001Co-Authors: Ichiro Maeda, Tomohiko Ohta, Hirotaka Koizumi, Mamoru FukudaAbstract:Overexpression of Cyclin D1 has been implicated in a variety of tumors, such as breast cancers, gastrointestinal cancers and lymphomas. Both gene amplification and protein degradation mediated by ubiquitin (Ub)-dependent proteolysis regulate the abundance of Cyclin D1. Here we report that ROC1 interacted with all three D type Cyclins in vivo but did not bind to other Cyclins tested. The ROC1–CUL1 and ROC1–CUL3, but not ROC1–CUL2, –CUL3 and –CUL4, immunocomplexes promoted polyubiquitination of bacterially purified Cyclin D1 in vitro. RING finger mutations of ROC1 eliminated the Ub ligase activity toward Cyclin D1. In all cases the ubiquitination of Cyclin D1 was accompanied by autoubiquitination of the cullins. The results suggest the involvement of ROC1–cullin ligases in Cyclin D1 ubiquitination and a potential mechanism whereby the cullin subunit is ubiquitinated itself while ubiquitinating a substrate.
Charles J Sherr - One of the best experts on this subject based on the ideXlab platform.
-
The D-Type Cyclins: A Historical Perspective
D-type Cyclins and Cancer, 2018Co-Authors: Charles J Sherr, Peter SicinskiAbstract:D-type Cyclins integrate mitogen-dependent signals to enforce progression through the first gap phase (G1) of the cell division cycle. In simplest terms, three mammalian D-type Cyclins (D1, D2, and D3), induced in a cell lineage-specific fashion in response to extracellular signals, interact with two Cyclin-dependent kinases (CDK4 and CDK6) to form holoenzyme complexes that phosphorylate the retinoblastoma protein (RB). In turn, RB phosphorylation, reinforced by other CDKs expressed later in G1 phase, inactivates the suppressive effects of RB on transcription factors that induce genes required for DNA replication. All steps in the life history of individual D-type Cyclins, including their transcriptional induction, translation, assembly with CDK4 and CDK6, and their rapid turnover via ubiquitin-mediated proteolysis, are governed by mitogen signaling. Hence, progression through the G1 phase of the mammalian cell cycle is tied to extracellular signals that ultimately influence cell division. Analysis of phenotypes of mice lacking D Cyclins has highlighted their individual and combinatorial lineage-specific activities during mammalian development. The genes encoding D-type Cyclins and their dependent kinases, CDK4 and CDK6, are proto-oncogenes implicated in many forms of cancer. Genetic or biochemical disruption of Cyclin D-dependent CDK signaling can restrain cancer development and progression. Here, we highlight the founding discoveries.
-
living with or without Cyclins and Cyclin dependent kinases
Genes & Development, 2004Co-Authors: Charles J Sherr, James M RobertsAbstract:Entry into, progression through, and exit from the G1 phase of the mammalian cell cycle in response to extracellular mitogenic cues are presumed to be governed by Cyclin-dependent kinases (Cdks) regulated by the D-type and E-type Cyclins. Studies performed over more than a decade have supported the view that these holoenzymes are important, if not required, for these processes. However, recent experiments in which the genes encoding all three D-type Cyclins, the two E-type Cyclins, Cyclin D-dependent Cdk4 and Cdk6, or Cyclin E-dependent Cdk2 have been disrupted in the mouse germ line have revealed that much of fetal development occurs normally in their absence. Thus, none of these genes is strictly essential for cell cycle progression. To what extent is the prevailing dogma incorrect, and how can the recent findings be reconciled with past work?
-
gene expression and cell cycle arrest mediated by transcription factor dmp1 is antagonized by d type Cyclins through a Cyclin dependent kinase independent mechanism
Molecular and Cellular Biology, 1998Co-Authors: Kazushi Inoue, Charles J SherrAbstract:A novel 761-amino-acid transcription factor, DMP1, contains a central DNA binding domain that includes three imperfect myb repeats flanked by acidic transactivating domains at the amino and carboxyl termini. D-type Cyclins associate with a region of the DMP1 DNA binding domain immediately adjacent to the myb repeats to form heteromeric complexes which detectably interact neither with Cyclin-dependent kinase 4 (CDK4) nor with DNA. The segment of D-type Cyclins required for its interaction with DMP1 falls outside the “Cyclin box,” which contains the residues predicted to contact CDK4. Hence, D-type Cyclin point mutants that do not interact with CDK4 can still bind to DMP1. Enforced coexpression of either of three D-type Cyclins (D1, D2, or D3) with DMP1 in mammalian cells canceled its ability to activate gene expression. This property was not shared by Cyclins A, B, C, or H; did not depend upon CDK4 or CDK2 coexpression; was not subverted by a mutation in Cyclin D1 that prevents its interaction with CDK4; and was unaffected by inhibitors of CDK4 catalytic activity. Introduction of DMP1 into mouse NIH 3T3 fibroblasts inhibited entry into S phase. Cell cycle arrest depended upon the ability of DMP1 to bind to DNA and to transactivate gene expression and was specifically antagonized by coexpression of D-type Cyclins, including a D1 point mutant that does not bind to CDK4. Taken together, these findings suggest that DMP1 induces genes that inhibit S phase entry and that D-type Cyclins can override DMP1-mediated growth arrest in a CDK-independent manner.
-
inhibition of Cyclin d1 phosphorylation on threonine 286 prevents its rapid degradation via the ubiquitin proteasome pathway
Genes & Development, 1997Co-Authors: J A Diehl, Frederique Zindy, Charles J SherrAbstract:: The expression of D-type G1 Cyclins and their assembly with their catalytic partners, the Cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), into active holoenzyme complexes are regulated by growth factor-induced signals. In turn, the ability of Cyclin D-dependent kinases to trigger phosphorylation of the retinoblastoma (Rb) protein in the mid- to late G1 phase of the cell cycle makes the inactivation of Rb's growth suppressive function a mitogen-dependent step. The ability of D-type Cyclins to act as growth factor sensors depends not only on their rapid induction by mitogens but also on their inherent instability, which ensures their precipitous degradation in cells deprived of growth factors. However, the mechanisms governing the turnover of D-type Cyclins have not yet been elucidated. We now show that Cyclin D1 turnover is governed by ubiquitination and proteasomal degradation, which are positively regulated by Cyclin D1 phosphorylation on threonine-286. Although "free" or CDK4-bound Cyclin D1 molecules are intrinsically unstable (t1/2 < 30 min), a Cyclin D1 mutant (T286A) containing an alanine for threonine-286 substitution fails to undergo efficient polyubiquitination in an in vitro system or in vivo, and it is markedly stabilized (t1/2 approximately 3.5 hr) when inducibly expressed in either quiescent or proliferating mouse fibroblasts. Phosphorylation of Cyclin D1 on threonine-286 also occurs in insect Sf9 cells, and although the process is enhanced significantly by the binding of Cyclin D1 to CDK4, it does not depend on CDK4 catalytic activity. This implies that another kinase can phosphorylate Cyclin D1 to accelerate its destruction and points to yet another means by which Cyclin D-dependent kinase activity may be exogenously regulated.
-
d type Cyclin dependent kinase activity in mammalian cells
Molecular and Cellular Biology, 1994Co-Authors: Hitoshi Matsushime, Charles J Sherr, Dawn E Quelle, S A Shurtleff, 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.
Ichiro Maeda - One of the best experts on this subject based on the ideXlab platform.
-
in vitro ubiquitination of Cyclin d1 by roc1 cul1 and roc1 cul3
FEBS Letters, 2001Co-Authors: Ichiro Maeda, Tomohiko Ohta, Hirotaka Koizumi, Mamoru FukudaAbstract:Overexpression of Cyclin D1 has been implicated in a variety of tumors, such as breast cancers, gastrointestinal cancers and lymphomas. Both gene amplification and protein degradation mediated by ubiquitin (Ub)-dependent proteolysis regulate the abundance of Cyclin D1. Here we report that ROC1 interacted with all three D type Cyclins in vivo but did not bind to other Cyclins tested. The ROC1–CUL1 and ROC1–CUL3, but not ROC1–CUL2, –CUL3 and –CUL4, immunocomplexes promoted polyubiquitination of bacterially purified Cyclin D1 in vitro. RING finger mutations of ROC1 eliminated the Ub ligase activity toward Cyclin D1. In all cases the ubiquitination of Cyclin D1 was accompanied by autoubiquitination of the cullins. The results suggest the involvement of ROC1–cullin ligases in Cyclin D1 ubiquitination and a potential mechanism whereby the cullin subunit is ubiquitinated itself while ubiquitinating a substrate.
-
In vitro ubiquitination of Cyclin D1 by ROC1–CUL1 and ROC1–CUL3
FEBS Letters, 2001Co-Authors: Ichiro Maeda, Tomohiko Ohta, Hirotaka Koizumi, Mamoru FukudaAbstract:Overexpression of Cyclin D1 has been implicated in a variety of tumors, such as breast cancers, gastrointestinal cancers and lymphomas. Both gene amplification and protein degradation mediated by ubiquitin (Ub)-dependent proteolysis regulate the abundance of Cyclin D1. Here we report that ROC1 interacted with all three D type Cyclins in vivo but did not bind to other Cyclins tested. The ROC1–CUL1 and ROC1–CUL3, but not ROC1–CUL2, –CUL3 and –CUL4, immunocomplexes promoted polyubiquitination of bacterially purified Cyclin D1 in vitro. RING finger mutations of ROC1 eliminated the Ub ligase activity toward Cyclin D1. In all cases the ubiquitination of Cyclin D1 was accompanied by autoubiquitination of the cullins. The results suggest the involvement of ROC1–cullin ligases in Cyclin D1 ubiquitination and a potential mechanism whereby the cullin subunit is ubiquitinated itself while ubiquitinating a substrate.
Tomohiko Ohta - One of the best experts on this subject based on the ideXlab platform.
-
in vitro ubiquitination of Cyclin d1 by roc1 cul1 and roc1 cul3
FEBS Letters, 2001Co-Authors: Ichiro Maeda, Tomohiko Ohta, Hirotaka Koizumi, Mamoru FukudaAbstract:Overexpression of Cyclin D1 has been implicated in a variety of tumors, such as breast cancers, gastrointestinal cancers and lymphomas. Both gene amplification and protein degradation mediated by ubiquitin (Ub)-dependent proteolysis regulate the abundance of Cyclin D1. Here we report that ROC1 interacted with all three D type Cyclins in vivo but did not bind to other Cyclins tested. The ROC1–CUL1 and ROC1–CUL3, but not ROC1–CUL2, –CUL3 and –CUL4, immunocomplexes promoted polyubiquitination of bacterially purified Cyclin D1 in vitro. RING finger mutations of ROC1 eliminated the Ub ligase activity toward Cyclin D1. In all cases the ubiquitination of Cyclin D1 was accompanied by autoubiquitination of the cullins. The results suggest the involvement of ROC1–cullin ligases in Cyclin D1 ubiquitination and a potential mechanism whereby the cullin subunit is ubiquitinated itself while ubiquitinating a substrate.
-
In vitro ubiquitination of Cyclin D1 by ROC1–CUL1 and ROC1–CUL3
FEBS Letters, 2001Co-Authors: Ichiro Maeda, Tomohiko Ohta, Hirotaka Koizumi, Mamoru FukudaAbstract:Overexpression of Cyclin D1 has been implicated in a variety of tumors, such as breast cancers, gastrointestinal cancers and lymphomas. Both gene amplification and protein degradation mediated by ubiquitin (Ub)-dependent proteolysis regulate the abundance of Cyclin D1. Here we report that ROC1 interacted with all three D type Cyclins in vivo but did not bind to other Cyclins tested. The ROC1–CUL1 and ROC1–CUL3, but not ROC1–CUL2, –CUL3 and –CUL4, immunocomplexes promoted polyubiquitination of bacterially purified Cyclin D1 in vitro. RING finger mutations of ROC1 eliminated the Ub ligase activity toward Cyclin D1. In all cases the ubiquitination of Cyclin D1 was accompanied by autoubiquitination of the cullins. The results suggest the involvement of ROC1–cullin ligases in Cyclin D1 ubiquitination and a potential mechanism whereby the cullin subunit is ubiquitinated itself while ubiquitinating a substrate.
Hirotaka Koizumi - One of the best experts on this subject based on the ideXlab platform.
-
in vitro ubiquitination of Cyclin d1 by roc1 cul1 and roc1 cul3
FEBS Letters, 2001Co-Authors: Ichiro Maeda, Tomohiko Ohta, Hirotaka Koizumi, Mamoru FukudaAbstract:Overexpression of Cyclin D1 has been implicated in a variety of tumors, such as breast cancers, gastrointestinal cancers and lymphomas. Both gene amplification and protein degradation mediated by ubiquitin (Ub)-dependent proteolysis regulate the abundance of Cyclin D1. Here we report that ROC1 interacted with all three D type Cyclins in vivo but did not bind to other Cyclins tested. The ROC1–CUL1 and ROC1–CUL3, but not ROC1–CUL2, –CUL3 and –CUL4, immunocomplexes promoted polyubiquitination of bacterially purified Cyclin D1 in vitro. RING finger mutations of ROC1 eliminated the Ub ligase activity toward Cyclin D1. In all cases the ubiquitination of Cyclin D1 was accompanied by autoubiquitination of the cullins. The results suggest the involvement of ROC1–cullin ligases in Cyclin D1 ubiquitination and a potential mechanism whereby the cullin subunit is ubiquitinated itself while ubiquitinating a substrate.
-
In vitro ubiquitination of Cyclin D1 by ROC1–CUL1 and ROC1–CUL3
FEBS Letters, 2001Co-Authors: Ichiro Maeda, Tomohiko Ohta, Hirotaka Koizumi, Mamoru FukudaAbstract:Overexpression of Cyclin D1 has been implicated in a variety of tumors, such as breast cancers, gastrointestinal cancers and lymphomas. Both gene amplification and protein degradation mediated by ubiquitin (Ub)-dependent proteolysis regulate the abundance of Cyclin D1. Here we report that ROC1 interacted with all three D type Cyclins in vivo but did not bind to other Cyclins tested. The ROC1–CUL1 and ROC1–CUL3, but not ROC1–CUL2, –CUL3 and –CUL4, immunocomplexes promoted polyubiquitination of bacterially purified Cyclin D1 in vitro. RING finger mutations of ROC1 eliminated the Ub ligase activity toward Cyclin D1. In all cases the ubiquitination of Cyclin D1 was accompanied by autoubiquitination of the cullins. The results suggest the involvement of ROC1–cullin ligases in Cyclin D1 ubiquitination and a potential mechanism whereby the cullin subunit is ubiquitinated itself while ubiquitinating a substrate.
