A Cyclin-Dependent Kinase-Activating Kinase (CAK) in Budding Yeast Unrelated to Vertebrate CAK

Espinoza, F. Hernán; Farrell, Alison; Erdjument‐Bromage, Hediye; Tempst, Paul; Morgan, David

doi:10.1126/science.273.5282.1714

Cited by 165 publications

(163 citation statements)

References 24 publications

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“…The CAK from S. cerevisiae was identified as Cak1, suggesting that budding yeast and vertebrates may have evolved different mechanisms of Cdk activation. The CAK and CTD kinase functions are split in budding yeast, with Kin28p as the kinase subunit of TFIIH and Cak1p as a CAK [10]. Similar mechanisms have been identified in S. prombe and Arabidopsis, where multiple CAKs are implicated in the regulation of Cdk and/or CTD phosphorylation [11,12].…”

Section: Introductionmentioning

confidence: 81%

Developmental expression of Cyclin H and Cdk7 in zebrafish: the essential role of Cyclin H during early embryo development

Liu

et al. 2007

Cell Res

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Cyclin-dependent kinase 7 (Cdk7) is the catalytic subunit of the metazoan Cdk-activating kinase (CAK). Activation of Cdk7 requires its association with a regulatory subunit, Cyclin H. Although the Cdk7/Cyclin H complex has been implicated in the regulation of RNA polymerase in several species, the precise function of their orthologs in zebrafish has not been fully elucidated. In this study, we isolated from zebrafish blastula embryos two cDNAs encoding the orthologs of human Cyclin H and Cdk7, and examined the role of Cdk7/Cyclin H in zebrafish embryogenesis. Sequence analysis showed that the zebrafish Cyclin H and Cdk7 cDNAs encode proteins with 65% and 86% identity to the respective human orthologs. RT-PCR and whole-mount in situ hybridization analyses of their expression in unfertilized eggs, embryos and organs of adult fish suggested that Cyclin H and Cdk7 messages are maternally loaded. Our data also showed that their transcripts were detected throughout development. Distribution of Cyclin H transcripts was found to be ubiquitous during early stages of development and become restricted to the anterior neural tube, brain, eyes, procreate tissues, liver and heart by 5 days post-fertilization. Expression of a dominant-negative form of Cyclin H delayed the onset of zygotic transcription in the early embryo, resulting in apoptosis at 5 hours post-fertilization and leading to sever defects in tissues normally exhibiting high levels of Cyclin H expression. These results implicate Cyclin H in the regulation of the transcriptional machinery during midblastula transition and suggest that it is an essential gene in early zebrafish larval development.

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Section: Introductionmentioning

confidence: 81%

Developmental expression of Cyclin H and Cdk7 in zebrafish: the essential role of Cyclin H during early embryo development

Liu

et al. 2007

Cell Res

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“…Another CAK activity, different from cdk7-cyclin H, could be localized in the cytoplasm. Indeed, a novel CAK (CAK1/civ1) has recently been identified as the physiologically relevant CAK in budding yeast (Espinoza et al, 1996;Kaldis et al, 1996;Thuret et al, 1996). Unlike the cdks, CAK1/civ1 is active as a monomer.…”

Section: Cyclin Hmentioning

confidence: 99%

“…The possible presence of Thr 161 phosphorylated monomeric cdc2 in the oocyte cytoplasm would be dependent on CAK other than cyclin H-cdk7. Interestingly, the CAK1/civ1 enzyme identified in budding yeast phosphorylates monomeric cdks as well as cyclin-cdk complexes (Espinoza et al, 1996;Kaldis et al, 1996;Thuret et al, 1996).…”

Section: Cyclin Hmentioning

confidence: 99%

On cyclins, oocytes, and eggs

1997

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Oocyte and egg are suitable model systems for studying cell division since meiotic maturation resembles a G2/M transition and early embryonic divisions are precisely timed and occur without zygotic transcription. The analysis of oocytes and eggs from different species provides the opportunity to understand the roles of proteins that are critical to the progression and maintenance of the cell cycle. Among them, cyclins are certainly worthy of investigation. Mitotic cyclins (cyclins A and B) are clearly implicated in meiosis and early embryonic cell cycles. More recent studies have revealed that G1‐type cyclins (cyclins E and D) could also play a role in both processes and cyclin H has been suggested to participate to CAK activity (cdc2‐activating kinase) in oocytes. The study of cyclins in oocytes and eggs clearly offer insights into their roles during the cell cycle. Mol. Reprod. Dev. 48:397–411, 1997. © 1997 Wiley‐Liss, Inc.

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“…Cak1p preferentially phosphorylates monomeric cdks; cyclin binding to cdks decreases phosphorylation by Cak1p (Kaldis et al, 1998;Brown et al, 1999). Furthermore, Cak1p phosphorylates and activates several human cdks (Espinoza et al, 1996;Kaldis et al, 1996Kaldis et al, , 1998Thuret et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…CDK7 prefers to phosphorylate cdk/cyclin complexes; monomeric cdks are poor substrates Kaldis et al, 1998). In contrast, the budding yeast CAK consists of a single, distantly related protein kinase, Cak1p (Espinoza et al, 1996;Kaldis et al, 1996;Thuret et al, 1996). Cak1p is an essential kinase that is responsible for phosphorylation and activation of the yeast cdk Cdc28p in vivo (Kaldis et al, 1996;Thuret et al, 1996).…”

mentioning

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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A Cyclin-Dependent Kinase-Activating Kinase (CAK) in Budding Yeast Unrelated to Vertebrate CAK

Cited by 165 publications

References 24 publications

Developmental expression of Cyclin H and Cdk7 in zebrafish: the essential role of Cyclin H during early embryo development

Developmental expression of Cyclin H and Cdk7 in zebrafish: the essential role of Cyclin H during early embryo development

On cyclins, oocytes, and eggs

CAK-independent Activation of CDK6 by a Viral Cyclin

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