ライフサイエンスコーパス: CDK8

1 II (Pol II), and cyclin-dependent kinase 8 (cdk8).

2 ely plays a role in the normal regulation of CDK8.

3 to interchromatin granule clusters and binds CDK8.

4 rough direct transcriptional upregulation of CDK8.

5 with a form of the Mediator complex lacking CDK8.

6 other transcription-related kinases CDK7 and CDK8.

7 t it was included in complexes with OrfA and cdk8.

8 dule, and contains a reduced amount of SRB10/CDK8.

9 cdk-2) that is conserved in all cdks except cdk8.

10 NA polymerase II and cyclin-dependent kinase CDK8.

11 and the human homolog of SRB7 in addition to CDK8.

12 anscription nearly as well as wild-type GAL4-CDK8.

13 Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of

14 Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with s

15 nt challenges to the clinical development of CDK8/19 inhibitors.

16 this will impact on the clinical utility of CDK8/19 inhibitors.

17 nt chemical probes with high selectivity for CDK8/19.

18 Thus, nuclear CDK8/9 drive a cycle of Smad utilization and disposal th

19 also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein.

20 Suppression of CDK8, a colorectal cancer oncogene, inhibits proliferati

21 rt that E1A and VP16 complexes contain human CDK8, a newly identified member of the cyclin-dependent

22 mendment, or depletion confirmed its role in CDK8 activation by triggering CDK8 autophosphorylation.

23 hospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mut

24 Although RV-cyclin and PP2A both enhance CDK8 activity, their actions are uncoupled and additive

25 eted HIV-1 Tat, suggesting that RNA-targeted Cdk8 acts on similar rate limiting post-initiation event

26 Together, these observations reveal that CDK8 acts, at least in part, through MYC to maintain bot

27 CDK8 affects beta-catenin activation by interaction of t

28 CDK8 also controls cellular responses to metabolic stimu

29 p21 and CDK8 also cooperate in the formation of internucleolar b

30 cancer cells characterized by high levels of CDK8 and beta-catenin hyperactivity.

31 MAM interacts directly with CDK8 and can cause it to localize to subnuclear foci.

32 CDK8 and CDK9 complexes, bound to viral activators E1A a

33 horylated at an interdomain linker region by CDK8 and CDK9, which are components of transcriptional m

34 ken together, these results demonstrate that CDK8 and CycC function as evolutionarily conserved compo

35 We find that Cdk8 and CycC interactions are stabilized within the Med

36 We observed that cdk8 and cycC mutants resemble EcR mutants and EcR-targe

37 The inhibitory effect of CDK8 and CycC on de novo lipogenesis was mediated throug

38 hysiologic regulation of lipid biosynthesis, CDK8 and CycC proteins were rapidly downregulated by fee

39 tified multiple Mediator subunits, including CDK8 and CycC.

40 of four subunits where Med12 and Med13 link Cdk8 and cyclin C (CycC) to core Mediator.

41 of Mediator complexes occur, one containing CDK8 and cyclin C and one lacking this CDK-cyclin pair.

42 cdk8 and cyclin C can regulate transcription via phospho

43 Mammalian cdk8 and cyclin C, and their respective yeast homologues

44 These results suggest that cyclin C/CDK8 and cyclin H/CDK7/p36 are physically distinct enzym

45 ificity is reflected in vivo where cyclin C/ CDK8 and cyclin H/CDK7/p36 can differentially phosphoryl

46 ve found that two of these kinases, cyclin C/CDK8 and cyclin H/CDK7/p36, can specifically phosphoryla

47 Here we show that CycC:CDK8 and CycT1:CDK9/P-TEFb are recruited with Notch and

48 n turn the two proteins cooperate to recruit CDK8 and enhance transcription initiation.

49 so looked at the transcriptional activity of CDK8 and found that CDK8 can function as a transcription

50 ibitors of a transcription-regulating kinase CDK8 and its isoform CDK19.

51 mental timing in Drosophila, is regulated by CDK8 and its regulatory partner Cyclin C (CycC), and the

52 teracts with EcR-USP in vivo; in particular, CDK8 and Med14 can directly interact with the AF1 domain

53 G promoters; RNAi knockdown of MED14 reduced CDK8 and RNA polymerase II (RNAPII) recruitment, RNAPII

54 T motif prevent hyperphosphorylation by CycC:CDK8 and stabilize the ICD in vivo.

55 Remarkably, p21 was found to bind to CDK8 and stimulate its kinase activity.

56 ssociated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-

57 It binds to cyclin-dependent kinase 8 (CDK8) and enhances its kinase activity.

58 th a unique cyclin dependent protein kinase (cdk8) and it has been proposed that this complex may reg

59 ere we identified cyclin-dependent kinase 8 (CDK8) and its regulatory partner cyclin C (CycC) as nega

60 d in coimmunoprecipitation of OrfA with anti-cdk8, and antiserum against OrfA was able to coprecipita

61 CDK7, CDK8, and CDK9 are cyclin-dependent kinases (CDKs) that

62 he cellular transcriptional machinery (CDK7, CDK8, and CDK9).

63 three cyclin-dependent kinases (CDKs): CDK7, CDK8, and CDK9.

64 y subcomplex consisting of the Med12, Med13, Cdk8, and Cyclin C subunits.

65 esidue is required for E2F1 interaction with CDK8, and that the phosphorylation is dependent on CDK8

66 the activity of the cyclin-dependent kinase Cdk8, and the tail module, which is required for positiv

67 ciates with a novel cyclin dependent kinase, CDK8, and we demonstrate that this complex is associated

68 Both Med220 and CDK8 (another subunit of TRAP/DRIP/ARC/Mediator) are rec

69 f the approximately 2-MDa fraction with anti-Cdk8 antibody indicated that at least two classes of Med

70 colon cancers and Drosophila have identified CDK8 as a colon cancer oncogene that regulates beta-cate

71 Here we show that a non-cdk8-associated cellular pool of cyclin C combines with

72 isordered region (IDR) both directs cyclin C-Cdk8 association and serves as the degron that mediates

73 ed its role in CDK8 activation by triggering CDK8 autophosphorylation.

74 dy establishes a critical role of Skp2-mH2A1-CDK8 axis in breast cancer development and targeting thi

75 macroH2A1 (mH2A1)-cyclin-dependent kinase 8 (CDK8) axis as a critical pathway for these processes, an

76 s to the highly conserved Myc Box I, whereas cdk8 binding localizes to the amino-terminal 41 amino ac

77 The Mediator-associated kinase CDK8, but not the paralog CDK19, is required for inducti

78 nscriptional activity of CDK8 and found that CDK8 can function as a transcriptional activator when fu

79 also identifies a biochemical means by which cdk8 can indirectly activate gene expression.

80 nic stem cell pluripotency state and loss of CDK8 caused embryonic stem cells to differentiate.

81 romotion and cancer progression (CDK1, CDK2, CDK8, CHEK1, CHEK2, GSK-3 beta, NPM, PAK1, PP2C-alpha).

82 associated with CTD kinase activity and that CDK8 co-fractionates with E1A- and VP16-associated CTD k

83 Thus, by retaining RB1 and amplifying CDK8, colorectal tumour cells select conditions that col

84 We further demonstrate that the cyclin C/CDK8 complex associates with the large subunit of RNA po

85 ve identified at least two distinct cyclin C/CDK8 containing complexes within the cell, a larger comp

86 CDK8 controls expression from highly regulated genes, in

87 This observation also revealed that Cdk8-CycC and Med12-Med13 often have opposite transcript

88 ression profiling demonstrated separation of Cdk8-CycC and Med12-Med13 profiles.

89 Consistently, CDK8-CycC interacts with EcR-USP in vivo; in particular,

90 hin the Mediator complex and the activity of Cdk8-CycC is regulated by other Mediator components.

91 Taken together, these results suggest that CDK8-CycC links nutrient intake to developmental transit

92 These results suggest that CDK8-CycC may serve as transcriptional cofactors for EcR

93 However, transcriptional regulation by Cdk8-CycC was dependent on Med12-Med13.

94 The Cdk8 (cyclin-dependent kinase 8) module of Mediator inte

95 Cyclin-dependent kinase 8 (CDK8), cyclin C, MED12, and MED13 form a variably associ

96 ship study of the cyclin-dependent kinase 8 (CDK8)/cyclin C (CycC) complex.

97 The four proteins CDK8, cyclin C, Med12, and Med13 can associate with Medi

98 The human CDK8 subcomplex (CDK8, cyclin C, Med12, and Med13) negatively regulates t

99 Here we show that cdk8/cyclin C can regulate transcription by targeting th

100 The cdk8/cyclin C protein complex is also found in a number

101 cells, but the RV-cyclin appears to activate CDK8 directly and in a manner independent of its physica

102 First, deleting its corepressor CDK8 does not suppress the slt2 hypersensitivity phenoty

103 larvae precociously increases the levels of CDK8, EcR and USP, yet down-regulates SREBP activity.

104 Phosphorylation by CDK8 enhanced SREBP-1c ubiquitination and protein degrad

105 lysis revealed striking correlations between CDK8 expression and poor survival in breast and ovarian

106 Consistent with this, we found that CDK8 expression correlated to the embryonic stem cell pl

107 Here we show that the suppression of CDK8 expression inhibits proliferation in colon cancer c

108 ificant inverse correlation between mH2A and CDK8 expression levels exists in melanoma patient sample

109 phase progression but mutations that release Cdk8 from CycC control also affect timing of entry into

110 serum against OrfA was able to coprecipitate cdk8 from lysates of cells that express OrfA.

111 yclin) represents a highly selected probe of CDK8 function.

112 RNAi experiments demonstrate that CDK8 functions as a coactivator within the p53 transcrip

113 ble to investigations of normal and abnormal CDK8 functions.

114 F complex whose degradation by Skp2 promotes CDK8 gene and protein expression.

115 The mammalian cyclin-dependent kinase 8 (cdk8) gene has been linked with a subset of acute lympho

116 r complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly

117 Here, we report that a Cdk8 homologue from Dictyostelium discoideum is localize

118 ion of MED12 with a second Mediator subunit, CDK8, identified herein to be a suppressor of GLI3 trans

119 tem cell-related genes that are activated by CDK8 in cancer.

120 feration of melanoma cells, and knockdown of CDK8 in cells depleted of mH2A suppresses the proliferat

121 iation in vivo and uncover a common role for CDK8 in controlling cancer and stem cell function.

122 o, implicating a potential role for cyclin C/CDK8 in regulating its activities.

123 The novel mechanism pinpoints CDK8 in the development of walleye dermal sarcoma and sh

124 The presence of CDK8 in the E1A- and VP16-containing complexes is specif

125 PP2A may be recruited to CDK8 in the Mediator complex by a specific PP2A B subuni

126 ese findings suggest a role for MAM and CycC:CDK8 in the turnover of the Notch enhancer complex at ta

127 ces the activity of immune affinity-purified CDK8 in vitro for RNA polymerase II carboxy-terminal dom

128 role of CycC, the cognate cyclin partner of Cdk8, in cell cycle control.

129 CDK8 inhibition offers a promising approach to increasin

130 A CDK8 inhibitor suppresses damage-induced tumor-promoting

131 mization of an imidazo-thiadiazole series of CDK8 inhibitors that was identified in a high-throughput

132 e genes implicated are TCF7L1, VAMP5, VAMP8, CDK8, INSIG2, IPF1, PAX8, IL18R1, members of the IL1 and

133 -catenin/TCF transcriptional complex, and by CDK8 interacting with and phosphorylating E2F1, which ac

134 t with active transcription, thus suggesting CDK8 involvement in transcriptional reinitiation.

135 CDK8 is a cyclin-dependent kinase that mediates transcri

136 ry partner Cyclin C (CycC), and the level of CDK8 is affected by nutrient availability.

137 We show that CDK8 is associated with CTD kinase activity and that CDK

138 CDK8 is dispensable for HIF1A chromatin binding and hist

139 We found that CDK8 is essential for robust T3-dependent Dio1 transcrip

140 CDK8 is evolutionarily conserved and is frequently overe

141 The PP2A enhancement of CDK8 is independent of RV-cyclin expression and likely p

142 Therefore, CDK8 is likely responsible for the E1A- and VP16-associa

143 Whereas CDK8 is linked to specific signaling cascades and oncoge

144 er with additional Mediator and RNAP II, but CDK8 is lost.

145 ndependent of transcriptional regulation, as Cdk8 is not required for this activity.

146 In this study, we show that CDK8 is required for both tumor growth and maintenance o

147 We showed that recruitment of cdk8 is sufficient for activation of a synthetic promote

148 cdk8 is the kinase partner of cyclin C and a component o

149 Finally, cyclin C, but not Cdk8, is required for loss of mitochondrial outer membra

150 , which encodes CDKE, a homolog of mammalian CDK8, is required for the specification of stamen and ca

151 l II CTD]) and novel (histone H3, Med13, and CDK8 itself) substrates for the CDK8 kinase.

152 The role of CDK7 and CDK8 kinase activity in transcription has been unclear,

153 PP2A also enhances CDK8 kinase activity in vitro for the CTD but not for hi

154 Mutagenesis assays showed that CDK8 kinase activity is necessary for full T3-dependent

155 for subcomplex-dependent repression, whereas CDK8 kinase activity is not.

156 nes, we observe that Mediator itself enables CDK8 kinase activity on chromatin, and we identify Med12

157 CDK8 kinase activity was necessary for beta-catenin-driv

158 t completely defined; past studies suggested CDK8 kinase activity was required for its repressive fun

159 h diverse targets imply strict regulation of CDK8 kinase activity.

160 and that the phosphorylation is dependent on CDK8 kinase activity.

161 EX-2 regulates assembly of Mediator with the Cdk8 kinase and is required for recruitment and site-spe

162 The yeast cyclin C-Cdk8 kinase forms a complex with Med13p to repress the t

163 ithin Mediator and its reversibly associated Cdk8 kinase module (CKM), we provide evidence that Media

164 These findings reveal that the Mediator CDK8 kinase module can promote non-ectodermal neurogenes

165 Both are members of the Cdk8 kinase module, which, with Med12 and Med13, associa

166 Cyclin C-Cdk8 kinase regulates transcription of diverse gene sets

167 ot Med13--to be essential for activating the CDK8 kinase.

168 , Med13, and CDK8 itself) substrates for the CDK8 kinase.

169 Moreover, cdk8 knockdown causes substantial reduction of global H3

170 ust T3-dependent Dio1 transcription and that CDK8 knockdown via RNA interference decreased Pol II occ

171 efeeding the starved larvae strongly reduces CDK8 levels but increases SREBP activity.

172 identify as Mediator-associated proteins the CDK8-like cyclin-dependent kinase CDK11 and the TRAP240-

173 Acute CDK8 loss in vivo strongly inhibited tumor growth and pr

174 Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colore

175 est that therapeutic interventions targeting CDK8 may confer a clinical benefit in beta-catenin-drive

176 ereas in vitro kinase studies indicated that CDK8 may contribute to Pol II phosphorylation.

177 This suggests that CDK8 may play a role in transcription that is distinct f

178 hree subunits of the CDK module of Mediator (CDK8, MED12, and cyclin C) are exclusively recruited dur

179 determined that Med12/Srb8, a member of the CDK8 Mediator submodule, is required for rho(0) activati

180 ciated with Cdk8(-) Mediator, during memory, Cdk8(+) Mediator recruits poised RNAPII PIC lacking the

181 inally, while active INO1 is associated with Cdk8(-) Mediator, during memory, Cdk8(+) Mediator recrui

182 mechanistic basis for GCN5L association with cdk8-Mediator and also identifies a biochemical means by

183 or suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation.

184 HIF1A induces binding of CDK8-Mediator and the super elongation complex (SEC), co

185 iption assay when Mediator was devoid of the Cdk8 module (CRSP).

186 here that Mediator complexes containing the CDK8 module are specifically recruited into preinitiatio

187 ly shown that two components of the Mediator CDK8 module encoded by CENTER CITY (CCT; Arabidopsis MED

188 The results reveal a novel role for the Cdk8 module in Serpent-dependent transcription and innat

189 e have investigated the contributions of the Cdk8 module subunits to transcriptional regulation using

190 MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 mo

191 y associated Mediator subcomplex (termed the CDK8 module) whose functional role in TR-dependent trans

192 ynamic interactions between Mediator and the CDK8 module, but the mechanisms governing CDK8 module-Me

193 Mediator subunits include the Cdk8 module, which has both positive and negative effect

194 ur work reveals a novel mechanism regulating CDK8 module-Mediator association and suggests an expande

195 he CDK8 module, but the mechanisms governing CDK8 module-Mediator association remain poorly understoo

196 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association.

197 is suppressed by the kinase activity of the Cdk8 module.

198 s activity of the cyclin-dependent kinase 8 (CDK8) module of the enigmatic "large Mediator" complex.

199 sponding increase in tail components seen in cdk8 mutants.

200 Chromatin immunoprecipitation revealed CDK8 occupancy at the DioI promoter concurrent with acti

201 The RV-cyclin increases CDK8 occupancy at the EGR1 gene locus before and after s

202 l and an unanticipated relationship with the CDK8 oncogene.

203 tion coincident with impaired recruitment of CDK8 onto promoters of GLI3-target genes, but not non-GL

204 h contains either cyclin-dependent kinase 8 (CDK8) or CDK19.

205 ctional levels of cyclin-dependent kinase-8 (CDK8) or its partner, cyclin C, have been clearly associ

206 The amino-acid residue in E2F1 that CDK8 phosphorylates and how this phosphorylation impacts

207 cdk8 phosphorylates mammalian cyclin H in the vicinity o

208 Here, we describe that CDK8 phosphorylates serine 375 in E2F1 both in vitro and

209 However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in tu

210 Purified recombinant CycC:CDK8 phosphorylates the Notch ICD within the TAD and PES

211 In addition, mimicking cdk8 phosphorylation of cyclin H in vivo has a dominant-

212 Here, cyclin C-Cdk8 phosphorylation of Med13 most likely primes the pho

213 on de novo lipogenesis was mediated through CDK8 phosphorylation of nuclear SREBP-1c at a conserved

214 he conserved cyclin C and its kinase partner Cdk8 play a key role in this decision.

215 Therefore, CDK8 plays a role in cell differentiation in a multicell

216 Collectively, our data suggest CDK8 plays an important coactivator role in TR-dependent

217 east strain reveals that CycC, together with Cdk8, primarily affects M-phase progression but mutation

218 Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription fr

219 g the larval-pupal transition, the levels of CDK8 protein positively correlate with EcR and USP level

220 rcoma cells (SJSA) are naturally depleted of CDK8 protein.

221 The Cdk8 proteins are kinases which phosphorylate the carbox

222 binding, lack of cyclin-dependent kinase 8 (CDK8) recruitment, and an attenuation of RNA polymerase

223 n tumor cells, and increased expression of a CDK8-regulated, embryonic stem cell MYC target gene sign

224 r complex-associated cyclin dependent kinase CDK8 regulates beta-catenin-dependent transcription foll

225 The phosphorylation of S375 by CDK8 regulates E2F1 ability to repress transcription of

226 We further show that CDK8 regulates p27 protein expression by facilitating Sk

227 Mediator contains the Cdk8 regulatory subcomplex, which directs periodic trans

228 other cellular Cdks, but a fusion of CycC to Cdk8 reported here did not cause any obvious cell cycle

229 occupied and carries Mediator containing the CDK8 repressive module, TFIID and RNAP II that is hypoph

230 iciency can be rescued by mH2A1 knockdown or CDK8 restoration using mouse tumour models.

231 ontrol CDK8 specificity but instead enhances CDK8's effects on regulated genes, an important distinct

232 of walleye dermal sarcoma and sheds light on CDK8's role in many human cancers.

233 (TAK/p-TEFb/Cdk9), our results indicate that Cdk8 shares with Cdk9 the ability to modulate transcript

234 was not dependent on the kinase activity of CDK8, since a kinase-deficient mutant of CDK8 stimulated

235 d3 interacts with, and is phosphorylated by, Cdk8; site-specific phosphorylation triggers interaction

236 RV-cyclin does not control CDK8 specificity but instead enhances CDK8's effects on

237 ologue (CycC/Srb11), cyclin-dependent kinase Cdk8/Srb10, and the large Med13/Srb9 protein.

238 subunits, including the negative regulators Cdk8/Srb10, Med5/Nut1, and Med15/Gal11 fail to derepress

239 tor from the inactive (Cdk8+) to the active (Cdk8-) state in RAR-dependent transcription.

240 of CDK8, since a kinase-deficient mutant of CDK8 stimulated transcription nearly as well as wild-typ

241 TAD and PEST domains, and expression of CycC:CDK8 strongly enhances Notch ICD hyperphosphorylation an

242 The human CDK8 subcomplex (CDK8, cyclin C, Med12, and Med13) negat

243 oscopy analysis suggests TRiC sequesters the CDK8 subcomplex and kinase assays reveal the endogenous

244 Collectively, these results reveal the CDK8 subcomplex functions as a simple switch that contro

245 Biochemical analysis of the recombinant CDK8 subcomplex identifies predicted (TFIIH and RNA poly

246 lation and enzymatic activity of the 600-kDa CDK8 subcomplex purified directly from human cells and a

247 mass spectrometry analysis of the endogenous CDK8 subcomplex reveals several associated factors, incl

248 Mediator and are presumed to form a stable "CDK8 subcomplex" in cells.

249 plex and kinase assays reveal the endogenous CDK8 subcomplex--unlike the recombinant submodule--is un

250 r but rather with Mediator that contains the cdk8 subcomplex.

251 stem together with recombinant or endogenous CDK8 subcomplexes, we demonstrate that, in fact, Med12 a

252 ructural and biochemical studies confirm the CDK8 submodule binds the Mediator leg/tail domain via th

253 The CDK8 submodule contains the cyclin C homologue (CycC/Srb

254 eta-catenin activation by interaction of the CDK8 submodule of the mediator complex with beta-catenin

255 Notably, the CDK8 submodule strongly represses even reinitiation even

256 o have variable effects on transcription and CDK8 suggested to repress transcription and/or to target

257 Also, Cdk8 targeted to RNA was observed to act in a synergysti

258 distinction for its use to delineate natural CDK8 targets.

259 matography using antibodies directed against CDK8, the human homolog of the yeast Srb10 protein.

260 es the intriguing possibility that targeting CDK8 therapeutically may specifically inhibit the stem-l

261 Surprisingly, the ability of GAL4-CDK8 to activate transcription in this assay was not dep

262 Furthermore, increased binding of CDK8 to p53 target genes correlates positively with tran

263 least partially, mediated by the ability of CDK8 to regulate MYC protein and downstream MYC target g

264 The flip of the DFG motif ("DMG" in CDK8) to the inactive DFG-out conformation appears to ha

265 nduced switch of Mediator from the inactive (Cdk8+) to the active (Cdk8-) state in RAR-dependent tran

266 zed the ability of a known CTD kinase, human Cdk8, to modulate HIV-1 LTR-driven gene expression upon

267 provide a mechanistic link between HIF1A and CDK8, two potent oncogenes, in the cellular response to

268 Importantly, Mediator was inactive (Cdk8+) under basal conditions but was activated (Cdk8-)

269 Mediator was retained in its inactive state (Cdk8+) upon induction consistent with the absence of gen

270 +) under basal conditions but was activated (Cdk8-) upon induction.

271 C inhibitor and gene promoter recruitment of CDK8 was found.

272 Similar regulation of MYC target genes by CDK8 was observed in colon tumor cells, and increased ex

273 The results indicated that Cdk8, when localized to an RNA element, activates gene e

274 One of these genes, CDK8, which encodes a member of the mediator complex, is

275 ctivation is the recently described oncogene CDK8, which is amplified in a large number of colorectal

276 ective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19.