ライフサイエンスコーパス: CDK8

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

2 to interchromatin granule clusters and binds CDK8.

3 rough direct transcriptional upregulation of CDK8.

4 with a form of the Mediator complex lacking CDK8.

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

6 CDK8/19 inhibition therefore increases Mediator-driven r

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

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

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

10 this can be achieved in vitro by inhibiting CDK8/19 kinase activity.

11 ical inhibition of CDK8 and CDK19 (hereafter CDK8/19) kinases removes their ability to repress the Me

12 conserved termini flank the metazoa-specific Cdk8/19-cyclin C binding region and are required for nor

13 actor, cyclin-dependent kinase 8/19-cyclinC (Cdk8/19-cyclin C), binds to a central domain of MTBP.

14 In the absence of MTBP binding to Cdk8/19-cyclin C, cells enter mitosis with incompletely

15 ic development coincides with a reduction in CDK8/19.

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

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

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

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

20 ors of ref4-3 and found that ref4-3 requires CDK8, a kinase module subunit of Mediator, to repress pl

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

22 y allow us to propose a revised model of how CDK8 activity is regulated by MED12, but also offer a pa

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

26 CDK8 affects beta-catenin activation by interaction of t

27 CDK8 also controls cellular responses to metabolic stimu

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

29 ected individuals fail to rescue the loss of Cdk8 and behave as null alleles.

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 Mechanistically, chemical inhibition of CDK8 and CDK19 (hereafter CDK8/19) kinases removes their

33 ellular transcription; our results implicate CDK8 and CDK19 as essential for this transcriptional rep

34 t STAT1-Ser727, a known CDK8 substrate, in a CDK8 and CDK19 CRISPR double-knockout cell line transfec

35 Unexpectedly, CDK8 and CDK19 regulated different gene sets via distinc

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

37 istone acetylation and recruitment of STAT3, CDK8 and cohesin.

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

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

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

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

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

43 tified multiple Mediator subunits, including CDK8 and CycC.

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

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

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

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

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

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

50 significant correlation between the level of CDK8 and of mTOR pathway members.

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

52 We discovered that both CDK8 and SnRK2.6 interact physically with an ERF/AP2 tra

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

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

55 binding of MED12 remodels the active site of CDK8 and thereby precludes the inhibition of ternary CDK

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

57 4 are orthologs of CYCLIN DEPENDENT KINASE8 (CDK8) and CYCLIN C1 (CYCC1), components of the CDK8 kina

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

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

60 the MED13, MED12, cyclin-dependent kinase 8 (CDK8), and cyclin C (CCNC) subunits.

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

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

63 combines mTOR inhibition and degradation of CDK8, and induces cell death in human leukemic cells.

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

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

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

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

68 Here, we demonstrated CDK8 as a critical regulator in the abscisic acid (ABA)

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

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

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

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

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

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

75 mechanistic insights into the activation of CDK8 by MED12.

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

77 We conclude that missense mutations in CDK8 cause a developmental disorder that has phenotypic

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

79 Finally, loss of Cdk8 causes an obvious loss of boutons and synapses at l

80 omposed of cyclin C and one each of paralogs Cdk8/Cdk19, Med12/Med12L, and Med13/Med13L.

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

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

83 thereby precludes the inhibition of ternary CDK8 complexes by type II kinase inhibitors.

84 ne transfected with wild-type (WT) or mutant CDK8 constructs.

85 CDK8 controls expression from highly regulated genes, in

86 ion of ABA-responsive genes, indicating that CDK8 could link the SnRK2.6-mediated ABA signaling to RN

87 As such, our work suggested that loss of CDK8 could overcome transcriptional and/or posttranscrip

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

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

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

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

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

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

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

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

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

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

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

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

100 on of the N-terminal segment of MED12 on the CDK8/Cyclin C complex and to gain mechanistic insights i

101 the mTOR signaling pathway is deregulated in CDK8-deficient cells and, accordingly, these cells are h

102 We propose that simultaneous CDK8 degradation and mTOR inhibition might represent a p

103 rs with specific binding sites promote rapid Cdk8-dependent Notch turnover, and thereby reduce Notch-

104 CDK8-dependent regulation required its kinase activity,

105 this enhancer induces Notch phenotypes in a Cdk8-dependent, transcription-independent manner.

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

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

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

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

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

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

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

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

114 an "activation helix" close to the T-loop of CDK8 for its activation.

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

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

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

118 ble to investigations of normal and abnormal CDK8 functions.

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

120 We provide evidence that CDK8 has a key role in B-ALL.

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

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

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

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

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

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

127 ionally, neuronal RNAi-mediated knockdown of Cdk8 in flies results in semi-lethality.

128 rd in developing small molecules that target CDK8 in its MED12-bound form.

129 Loss of CDK8 in leukemia mouse models significantly enhances dis

130 data provide new insights into the roles of CDK8 in modulating ABA signaling and drought responses.

131 However, the biological functions of CDK8 in plant abiotic stress responses remain largely un

132 rthermore, our work also implicated FCP1 and CDK8 in the broader response to environmental stressors

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

134 t human CDK19 fully replaces the function of Cdk8 in the fly, the human disease-associated CDK19 vari

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

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

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

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

139 CDK8 inhibition offers a promising approach to increasin

140 A CDK8 inhibitor suppresses damage-induced tumor-promoting

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

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

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

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

145 CDK8 is a cyclin-dependent kinase that mediates transcri

146 CDK8 is a key subunit of Mediator complex, a large multi

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

148 Loss of CDK8 is associated with pronounced transcriptional chang

149 CDK8 is dispensable for HIF1A chromatin binding and hist

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

151 Importantly, we also showed that CDK8 is essential for the ABA-induced expression of RAP2

152 CDK8 is evolutionarily conserved and is frequently overe

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

154 Whereas CDK8 is linked to specific signaling cascades and oncoge

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

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

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

158 Cyclin C-cyclin-dependent kinase (Cdk8) is a component of the RNA polymerase II Mediator c

159 s catalytic core, cyclin-dependent kinase 8 (CDK8), is controlled by Cyclin C and regulatory subunit

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

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

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

163 transcriptional changes, whereas inhibiting CDK8 kinase activity has minimal effects.

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

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

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

167 Using inhibitors, we found that Cdk8 kinase activity is not required for CKM movement or

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

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

170 ar run-on sequencing (PRO-seq), we show that CDK8 kinase activity promotes RNA polymerase II pause re

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

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

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

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

175 ically separated in ref4-3 by elimination of CDK8 kinase activity; however, the stunted growth of ref

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

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

178 actor (TF) during IFN-gamma stimulation, and CDK8 kinase inhibition blocked activation of JAK-STAT pa

179 The Cdk8 kinase module (CKM) is a detachable Mediator subuni

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

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

182 K8) and CYCLIN C1 (CYCC1), components of the CDK8 kinase module of the Mediator complex, which is a d

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

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

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

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

187 Moreover, cdk8 knockdown causes substantial reduction of global H3

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

205 ts establish the conserved importance of the CDK8 module in plants and provide evidence for the funct

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

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

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

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

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

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

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

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

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

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

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

217 Compared to wild-type, cdk8 mutants showed reduced sensitivity to ABA, impaired

218 sponding increase in tail components seen in cdk8 mutants.

219 Here, we report CDK8 mutations (located at 13q12.13) that cause a phenot

220 Accordingly, CDK8, not CDK19, phosphorylates the STAT1 transcription

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

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

223 l and an unanticipated relationship with the CDK8 oncogene.

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

225 ociation of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or

226 The Mediator kinase module contains CDK8 or CDK19, which are presumed to be functionally red

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

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

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

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

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

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

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

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

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

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

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

238 n immunoprecipitation analysis revealed that CDK8 positively regulates the transcription of several A

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

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

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

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

243 The Cdk8 proteins are kinases which phosphorylate the carbox

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

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

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

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

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

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

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

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

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

253 Interestingly, loss of CDK8 robustly normalized the mRNA levels of Skn7-depende

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

275 Notably, the CDK8 submodule strongly represses even reinitiation even

276 tified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de

277 red phosphorylation at STAT1-Ser727, a known CDK8 substrate, in a CDK8 and CDK19 CRISPR double-knocko

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

279 distinction for its use to delineate natural CDK8 targets.

280 Loss of Cdk8, the fly homolog of CDK19, causes larval lethality,

281 fcp1 mutants revealed a novel connection to Cdk8, the Mediator complex kinase subunit, and Skn7, a k

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

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

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

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

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

287 Here we report that cyclin C-Cdk8, together with the Ume6-Rpd3 histone deacetylase co

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

289 ion of fcp1 mutant growth defects by loss of CDK8 under oxidative stress conditions.

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

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

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

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

294 The genetic interaction between MED5 and CDK8 was further characterized using mRNA-sequencing (RN

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

296 the N-terminal portion of MED12 wraps around CDK8, whereby it positions an "activation helix" close t

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

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

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

300 rs do not diminish the affinity of MED12 for CDK8, yet likely alter the exact positioning of the acti