Cdk-activating kinase complex is a component of human transcription factor TFIIH

Shiekhattar, Ramin; Mermelstein, Fred H.; Fisher, Robert P; Drapkin, Ronny; Dynlacht, Brian David; Wessling, H C; Morgan, David; Reinberg, Danny

doi:10.1038/374283a0

Cited by 420 publications

(319 citation statements)

References 16 publications

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“…HINT enzyme activity is a positive regulator of Kin28, the human homologue is CDK7 (21). Human CDK7 interacts with the transcriptional machinery in the nucleus (22). There are likely a variety of substrates/target proteins for Hint and Aprataxin that regulate a variety of cellular processes.…”

Section: Hint1mentioning

confidence: 99%

Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia

et al. 2004

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Microarray expression studies have reported decreased mRNA expression of histidine triad nucleotide-binding protein (HINT1) and cytosolic malate dehydrogenase (MDH1) in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. Microarray results for neuroserpin (SERPINI1) mRNA in the DLPFC have reported increased and decreased expression in individuals with schizophrenia. The relative abundances of HINT1, MDH1, and SERPINI1 mRNA in the DLPFC in individuals with schizophrenia and controls were measured by real-time quantitative polymerase chain reaction (Q-PCR) and for HINT1 expression by in situ hybridization. The Q-PCR results were compared by analysis of covariance between individuals with schizophrenia and controls. Gene expression levels for HINT1, MDH1, and SERPINI1 were significantly different between the groups. The male individuals with schizophrenia compared to male controls showed reductions by 2.8-to 3.7-fold of HINT1, neuroserpin, and MDH1 by Q-PCR. The decreases in mRNA abundance for MDH1 (P ϭ 0.006), HINT1 (P ϭ 0.050), and neuroserpin (P ϭ 0.005) in DLPFC of male individuals with schizophrenia is consistent with prior reports. HINT1 mRNA was reduced significantly by 34% in layer VI. Though there were no significant interactions with gender, gene expression between female patients and the female control group did not differ. These results confirm earlier reports and suggest abnormalities of specific genes related to metabolic and protease activities in the DLPFC might be considered as part of a molecular pathway in male patients with schizophrenia.

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Section: Hint1mentioning

confidence: 99%

Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia

et al. 2004

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“…Other experiments are clearly needed before concluding that cdk7-cyclin H is the biologically relevant CAK. Since it has been shown that cdk7-cyclin H-MAT-1 complexes are a component of the transcription factor TFIIH in mammalian cells (Roy et al, 1994;Serizawa et al, 1995;Shiekhattar et al, 1995), their role could be restricted to the regulation of RNA polymerase II-dependent transcription and nucleotideexcision repair of DNA, some of the functions achieved by TFIIH (Draetta, 1997;Fisher and Morgan, 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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“…In species other than budding yeast, CAK is composed of a catalytic subunit, CDK7 (Fesquet et al, 1993;Poon et al, 1993;Solomon et al, 1993;Tassan et al, 1994; also called MO15); a regulatory subunit, cyclin H Mäkelä et al, 1994); and an assembly factor, MAT1 (Devault et al, 1995;Fisher et al, 1995;Tassan et al, 1995). All three of these proteins have also been found to be subunits of the general transcription factor TFIIH (Roy et al, 1994;Serizawa et al, 1995;Shiekhattar et al, 1995;Adamczewski et al, 1996), which phosphorylates the C-terminal domain (CTD) of the large subunit of RNA polymerase II. CDK7 prefers to phosphorylate cdk/cyclin complexes; monomeric cdks are poor substrates Kaldis et al, 1998).…”

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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Cdk-activating kinase complex is a component of human transcription factor TFIIH

Cited by 420 publications

References 16 publications

Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia

Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia

On cyclins, oocytes, and eggs

CAK-independent Activation of CDK6 by a Viral Cyclin

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