A- and B-type cyclins differentially modulate substrate specificity of cyclin-cdk complexes.

Peeper, Daniel S.; Parker, Laura L.; Ewen, Mark E.; Toebes, Mireille; Hall, Frederick L.; Xu, Min; Zantema, A.; Eb, Abramova; Piwnica‐Worms, Helen

doi:10.1002/j.1460-2075.1993.tb05844.x

Cited by 191 publications

(126 citation statements)

References 58 publications

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“…Activity of E2F-1 in DNA binding and transcription is enhanced by forming a heterodimeric complex with DP-1 (48). Phosphorylation of E2F-1 on Ser 323 and Ser 337 prevents its interaction with RB, regardless of the phosphorylation status of RB (49), whereas phosphorylation of E2F-1 on Ser 375 , a specific CDK site, promotes RB binding (50). Acetylation of E2F-1 can augment its own DNA binding activity, increase its transcriptional activity, and prolong its half-life (51).…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor α Inhibits Cyclin A Expression and Retinoblastoma Hyperphosphorylation Triggered by Insulin-like Growth Factor-I Induction of New E2F-1 Synthesis

Shen

Yin

Broussard

et al. 2004

Journal of Biological Chemistry

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Cyclin A is required for cell cycle S phase entry, and its overexpression contributes to tumorigenesis. Release of pre-existing E2Fs from inactive complexes of E2F and hypophosphorylated retinoblastoma (RB) is the prevailing dogma for E2F transcriptional activation of target genes such as cyclin A. Here we explored the hypothesis that new synthesis of E2F-1 is required for insulin-like growth factor-I (IGF-I) to induce cyclin A accumulation and RB hyperphosphorylation, events that are targeted by tumor necrosis factor ␣ (TNF␣) to arrest cell cycle progression. We first established that IGF-I increases expression of cyclin A, causes hyperphosphorylation of RB, and augments the mass of E2F-1 in a time-dependent manner. As expected, E2F-1 small interfering RNA blocks the ability of IGF-I to increase synthesis of E2F-1. Most important, this E2F-1 small interfering RNA also blocks the ability of IGF-I to increase cyclin A accumulation and to hyperphosphorylate RB. We next established that TNF␣ dose-dependently inhibits IGF-I-induced phosphorylation of both RB and histone H1 by cyclin A-dependent cyclin-dependent kinases. Cyclin-dependent kinase 2 (Cdk2) mediates this suppression because co-immunoprecipitation experiments revealed that TNF␣ reduces the amount of IGF-Iinduced cyclin A that binds Cdk2, leading to a reduction in Cdk2 enzymatic activity. TNF␣ antagonizes the ability of IGF-I to increase mass of both E2F-1 and cyclin A but not cyclin E or D1. The cytostatic property of TNF␣ is also shown by its ability to block IGF-I-stimulated luciferase activity of a cyclin A promoter reporter. Deletion of an E2F recognition site from this reporter eliminates the regulatory effects of both IGF-I and TNF␣ on cyclin A transcription, indicating the essential role of E2F-1 in mediating their cross-talk. Collectively, these results establish that TNF␣ targets IGF-I-induced E2F-1 synthesis, leading to inhibition of the subsequent accumulation in cyclin A, formation of cyclin A-Cdk2 complexes, hyperphosphorylation of RB, and cell cycle arrest.

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Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor α Inhibits Cyclin A Expression and Retinoblastoma Hyperphosphorylation Triggered by Insulin-like Growth Factor-I Induction of New E2F-1 Synthesis

Shen

Yin

Broussard

et al. 2004

Journal of Biological Chemistry

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“…Transcriptional control (Koch and Nasmyth, 1994) and ubiquitin-mediated degradation (King et al, 1996) ensure the proper and irreversible timing of cell cycle regulatory events. Cyclins have also been shown to affect the substrate specificity of cdks (Peeper et al, 1993;Kelly et al, 1998;Schulman et al, 1998;Cross et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

CAK-independent Activation of CDK6 by a Viral Cyclin

Kaldis

Ojala

Tong

et al. 2001

MBoC

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In normal cells, activation of cyclin-dependent kinases (cdks) requires binding to a cyclin and phosphorylation by the cdk-activating kinase (CAK). The Kaposi's sarcoma-associated herpesvirus encodes a protein with similarity to D-type cyclins. This KSHV-cyclin activates CDK6, alters its substrate specificity, and renders CDK6 insensitive to inhibition by the cdk inhibitor p16 INK4a . Here we investigate the regulation of the CDK6/KSHV-cyclin kinase with the use of purified proteins and a cell-based assay. We find that KSHV-cyclin can activate CDK6 independent of phosphorylation by CAK in vitro. In addition, CAK phosphorylation decreased the p16 INK4a sensitivity of CDK6/KSHV-cyclin complexes. In cells, expression of CDK6 or to a lesser degree of a nonphosphorylatable CDK6 T177A together with KSHV-cyclin induced apoptosis, indicating that CDK6 activation by KSHV-cyclin can proceed in the absence of phosphorylation by CAK in vivo. Coexpression of p16 partially protected cells from cell death. p16 and KSHV-cyclin can form a ternary complex with CDK6 that can be detected by binding assays as well as by conformational changes in CDK6. The Kaposi's sarcoma-associated herpesvirus has adopted a clever strategy to render cell cycle progression independent of mitogenic signals, cdk inhibition, or phosphorylation by CAK. INTRODUCTIONThe sequential activation of cyclin-dependent kinases (cdks) promotes cell cycle transitions. CDK4 and CDK6 bind to D-type cyclins and are active in G1, CDK2/cyclin E complexes function in late G1, CDK2/cyclin A complexes function in S phase, and CDC2/cyclin B and A complexes function in G2/M. The activities of cdks are regulated by protein-protein interactions (with cyclins, inhibitors, and assembly factors), protein degradation, transcriptional control, subcellular localization, and multiple phosphorylations (Pines, 1995;Sherr and Roberts, 1995;King et al., 1996;Solomon and Kaldis, 1998). Viral infection frequently targets downstream targets of cdks, resulting in inappropriate cell cycle progression.Cyclin binding activates cdks by inducing conformational changes in the structure of cdks (Jeffrey et al., 1995;Pavletich, 1999). Cyclins are unstable proteins that are synthesized and degraded periodically during the cell cycle. Transcriptional control (Koch and Nasmyth, 1994) and ubiquitin-mediated degradation (King et al., 1996) ensure the proper and irreversible timing of cell cycle regulatory events. Cyclins have also been shown to affect the substrate specificity of cdks (Peeper et al., 1993;Kelly et al., 1998;Schulman et al., 1998;Cross et al., 1999).Maximal activation of cdks requires phosphorylation of certain residues as well as dephosphorylation of others. The dual-specificity phosphatase CDC25 removes phosphates from inhibitory phosphorylation sites (Thr-14 and Tyr-15 in human CDK2) that have been phosphorylated by the WEE1/MYT1 protein kinases . Phosphorylation of an activating threonine (Thr-160 in CDK2 and Thr-177 in CDK6) by the cdk-activating kinase (CAK; reviewed by Kaldis, 199...

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“…In addition to the interactions with the D cyclins, p107 and p130 stably interact with cyclin A/cdk2 and cyclin E/cdk2 complexes in vivo and in vitro Faha et al, 1992Faha et al, , 1993Lees et al, 1992;Hannon et al, 1993;Li et al, 1993;Peeper et al, 1993). This property is not held in common with pRB and the signi®cance of this di erence remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Identification of a p130 domain mediating interactions with cyclin A/cdk 2 and cyclin E/cdk 2 complexes

Lacy

Whyte

1997

Oncogene

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A- and B-type cyclins differentially modulate substrate specificity of cyclin-cdk complexes.

Cited by 191 publications

References 58 publications

Tumor Necrosis Factor α Inhibits Cyclin A Expression and Retinoblastoma Hyperphosphorylation Triggered by Insulin-like Growth Factor-I Induction of New E2F-1 Synthesis

Tumor Necrosis Factor α Inhibits Cyclin A Expression and Retinoblastoma Hyperphosphorylation Triggered by Insulin-like Growth Factor-I Induction of New E2F-1 Synthesis

CAK-independent Activation of CDK6 by a Viral Cyclin

Identification of a p130 domain mediating interactions with cyclin A/cdk 2 and cyclin E/cdk 2 complexes

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