ライフサイエンスコーパス: CDK4

1 interaction with cyclin-dependent kinase 4 (CDK4).

2 ight specifically initiate the activation of CDK4.

3 for cancer genes like MYC, STK11, RASSF1 and CDK4.

4 Here, we show that cyclin D-Cdk4,6 docks one side of an alpha-helix in the Rb C term

5 horylated by other cyclin-Cdks, and cyclin D-Cdk4,6 has other targets involved in cell division.

6 , the role of Rb phosphorylation by cyclin D-Cdk4,6 in cell-cycle progression is unclear because Rb c

7 A well-known target of cyclin D-Cdk4,6 is the retinoblastoma protein Rb, which inhibits

8 ss of the CDKN2A tumor suppressor locus make CDK4/6 a potential target in pancreatic ductal adenocarc

9 oved for a breast cancer subtype addicted to CDK4/6 activation, could be repurposed to treat SCCOHT.

10 on of G1 length by temporary inactivation of CDK4/6 activity after mitosis, and a progressively incre

11 y the familial melanoma CDKN2 locus) inhibit CDK4/6 activity and have important roles in cellular sen

12 CDK2 activity gradually increases, and that CDK4/6 activity can be active after mitosis or inactive

13 deletions, and amplifications that increase CDK4/6 activity contribute to the progression of many ca

14 ort-term memory, or transient hysteresis, in CDK4/6 activity following mitogen removal that sustains

15 K2 activities in single cells and found that CDK4/6 activity increases rapidly before CDK2 activity g

16 CDK4/6 activity is clinically relevant as mutations, del

17 nd a progressively increasing persistence in CDK4/6 activity that restricts cells from returning to q

18 n removal in G1 results in a gradual loss of CDK4/6 activity with a high likelihood of cells sustaini

19 on starting at the onset of S phase and that CDK4/6 activity, but not cyclin E/A-CDK activity, is req

20 Surprisingly, with low CDK4/6 activity, the order of APC/C(CDH1) and Rb inactiv

21 r steps that enable cell-cycle entry without CDK4/6 activity.

22 istance to clinical inhibitors of MEK1/2 and CDK4/6 alone and in combination.

23 on of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib.

24 ctivities by targeting cell cycle regulators CDK4/6 and anti-apoptotic factor BCL-2, among other regu

25 Furthermore, we demonstrate that CDK4/6 and CDK1 play a key role not only in the transiti

26 a reporter system to simultaneously monitor CDK4/6 and CDK2 activities in single cells and found tha

27 nhibitor ratio for ultrasensitive control of CDK4/6 and CDK2.

28 nalysis to identify novel miRNAs that target CDK4/6 and exhibit potential for therapeutic development

29 sidered for trials using combinations of ER, CDK4/6 and FGFR antagonists.

30 verse relationship between the expression of CDK4/6 and miR-149* and intronic miRNA-6883-5p encoding

31 rther investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but ot

32 de preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated ther

33 The extent to which cancers depend on CDK4/6 and the mechanisms that may undermine such depend

34 elanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.

35 Cyclin D-CDK4/6 are the first cyclin-dependent kinase (CDK) compl

36 g cell cycle G1 arrest through inhibition of CDK4/6 associated with the upregulation of HBV transcrip

37 trate convergent mechanisms of PI3Kalpha and CDK4/6 blockade on cell-cycle progression, DNA damage re

38 f BRD4 and the kinase activities of PI3K and CDK4/6 by the TP inhibitor improves efficacy in several

39 Inhibition of CDK4/6 can result in different cell fates such as quiesc

40 or proliferation and sensitive to MEK1/2 and CDK4/6 combination treatment.

41 Transcriptomic profiling of CDK4/6 CRISPR knockouts in breast cancer revealed these

42 ines, combined IKZF1/3 degradation with dual CDK4/6 degradation produced enhanced anti-proliferative

43 ative effects compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3 degradation.

44 Combined inhibition of MET/FAK and CDK4/6 eliminates the proliferation capacity of cancer c

45 emonstrate that cells with acutely inhibited CDK4/6 enter the cell cycle with a slowed and fluctuatin

46 ct was comparable or superior to that of the CDK4/6 enzymatic inhibitor palbociclib.

47 ted as a novel PET imaging agent to quantify CDK4/6 expression in estrogen receptor (ER)-positive hum

48 n: (18)F-CDKi represents the first (18)F PET CDK4/6 imaging agent and a promising imaging agent for E

49 revealed a significantly lower activation of CDK4/6 in nontargeting organs.

50 s to profile the immunopeptidome response to CDK4/6 inhibition and interferon-gamma - known modulator

51 rmore, SMARCA4 loss is synthetic lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting

52 c ablation of NRAS or combination MEK1/2 and CDK4/6 inhibition by upregulating activity of the RTK-RA

53 Analysis of these cells revealed that CDK4/6 inhibition failed to induce cell-cycle arrest or

54 on status of CDK2, which was suppressed with CDK4/6 inhibition in an RB-dependent fashion.

55 Gemcitabine largely ablates the function of CDK4/6 inhibition in S-phase arrested cells when adminis

56 or further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms o

57 cooperative effects between chemotherapy and CDK4/6 inhibition in vivo.

58 Combined PI3Kalpha and CDK4/6 inhibition significantly increased apoptosis, cel

59 Combined PI3Kalpha and CDK4/6 inhibition significantly increased tumor-infiltra

60 creatic cancers have intrinsic resistance to CDK4/6 inhibition that is not due to any established mec

61 ccordingly, the antiproliferative effects of CDK4/6 inhibition were synergistic with HIF-2alpha inhib

62 Notably, combined PI3Kalpha and CDK4/6 inhibition, along with inhibition of immune check

63 induced luminal breast cancer resistance to CDK4/6 inhibition, both in vitro and in vivo.

64 anced anti-proliferative effects compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3 degrad

65 ell cycle and correlated with sensitivity to CDK4/6 inhibition.

66 rks that can be exploited upon relapse after CDK4/6 inhibition.

67 n D1 deficiency leading to susceptibility to CDK4/6 inhibition.

68 ors that drive plasticity and sensitivity to CDK4/6 inhibition.

69 distinct effects on the cellular response to CDK4/6 inhibition.

70 om S-phase block they exhibit sensitivity to CDK4/6 inhibition.

71 lectively modulates Mcl-1 function while the CDK4/6 inhibitor 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(p

72 s or older (n = 198) who were treated with a CDK4/6 inhibitor and an AI, hazard ratio was 0.49 (95% C

73 ulnerability to combinatorial treatment with CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo

74 Consistent with circadian regulation, a CDK4/6 inhibitor approved for cancer treatment reduced g

75 egies include deepening cell cycle exit with CDK4/6 inhibitor combinations, selectively targeting tum

76 This tankyrase inhibitor-CDK4/6 inhibitor combinatorial effect is not limited to

77 a rationale for the clinical application of CDK4/6 inhibitor combinatorial regimens for patients wit

78 There was similar efficacy with a CDK4/6 inhibitor in combination with an AI compared with

79 Addition of the CDK4/6 inhibitor LEE011 to BYL719 caused a simultaneous

80 olonged exposure to the selective and potent CDK4/6 inhibitor LY2835219, clones emerged and several w

81 Utilizing remote loading to co-encapsulate CDK4/6 inhibitor palbociclib (PAL) and an autophagy inhi

82 lanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the ac

83 l cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resi

84 Moreover, coadministration of the CDK4/6 inhibitor palbociclib in combination with H3B-652

85 ents with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the impo

86 more effective than treatment with the dual CDK4/6 inhibitor palbociclib in suppressing Ph+ ALL in m

87 The CDK4/6 inhibitor palbociclib reduces tumor growth by dec

88 sensitivity screens showed that the clinical CDK4/6 inhibitor palbociclib, causes enhanced sensitivit

89 he combination of anti-HER2/neu antibody and CDK4/6 inhibitor Palbociclib.

90 te assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness.

91 inome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identif

92 CDKN2A/2B loss as a biomarker predictive of CDK4/6 inhibitor sensitivity.

93 nd indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity.

94 ally loses CDKN2A that encodes an endogenous CDK4/6 inhibitor to bypass the RB-mediated cell cycle su

95 ously reported that palbociclib (a selective CDK4/6 inhibitor) given with cetuximab (an EGFR inhibito

96 Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibito

97 a tractable route to broaden the utility of CDK4/6 inhibitor-based therapies in the clinic.

98 les a sustained control of the fast-evolving CDK4/6 inhibitor-resistant tumors.

99 e selectively upregulated by RB knockdown or CDK4/6 inhibitor.

100 ment with AI alone or with the addition of a CDK4/6 inhibitor.

101 harbor a durable response to monotherapy of CDK4/6 inhibitor.

102 First, CDK4/6 inhibitors activate tumour cell expression of end

103 demonstrate that treatment with CDK4/6 inhibitors after application of taxanes (or other

104 we report that sequential administration of CDK4/6 inhibitors after taxanes cooperates to prevent ce

105 ls are currently investigating if the use of CDK4/6 inhibitors alone or in combination can be extende

106 CDK4/6 inhibitors also prevent recovery from multiple DN

107 Combination of CDK4/6 inhibitors and endocrine therapy improves clinica

108 nale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti-cancer tre

109 resent a predictive biomarker of response to CDK4/6 inhibitors and its loss could identify DCIS lesio

110 tential for using combination treatment with CDK4/6 inhibitors and PD-1-PD-L1 immune checkpoint block

111 ib and MSC2504877 and is elicited with other CDK4/6 inhibitors and toolbox tankyrase inhibitors.

112 ancers, and specific cyclin-dependent kinase Cdk4/6 inhibitors are approved or in clinical trials for

113 While CDK4/6 inhibitors are FDA approved (palbociclib) for tre

114 inical studies indicate that pharmacological CDK4/6 inhibitors are only modestly effective.

115 CDK4/6 inhibitors are used to treat estrogen receptor (E

116 Further studies of CDK4/6 inhibitors are warranted in HPV-unrelated HNSCC.

117 These findings support testing CDK4/6 inhibitors as treatments for ccRCC, alone and in

118 ro and in vivo, suggesting that FDA-approved CDK4/6 inhibitors could be effective to treat this signi

119 ing and refining the clinical application of CDK4/6 inhibitors for patients with breast cancer.

120 f the cell cycle, and there are FDA-approved CDK4/6 inhibitors for treating patients with metastatic

121 Combination treatment with MTOR and CDK4/6 inhibitors had potent activity across a large num

122 r acquired resistance to clinically approved CDK4/6 inhibitors has emerged as a major obstacle that h

123 CDK4/6 inhibitors have emerged as the most promising of

124 To date, CDK4/6 inhibitors have shown promising clinical activity

125 (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or ac

126 Indeed, CDK4/6 inhibitors in combination with antiestrogens prod

127 dies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and th

128 ng, combinatorial strategies, and the use of CDK4/6 inhibitors in the adjuvant and neoadjuvant settin

129 cy in ESCC cells with acquired resistance to CDK4/6 inhibitors in vitro and in xenograft tumors.

130 Our findings indicate that CDK4/6 inhibitors increase tumour immunogenicity and pro

131 b, and that the combination of autophagy and CDK4/6 inhibitors induces irreversible growth inhibition

132 Overall, we show that resistance to CDK4/6 inhibitors is dependent on kinase re-wiring and t

133 Second, CDK4/6 inhibitors markedly suppress the proliferation of

134 t correlates with the repressive activity of CDK4/6 inhibitors on homologous recombination proteins r

135 n the dependence of specific Wnt, Notch, and CDK4/6 inhibitors on PRH activity.

136 In the first-line or second-line setting, CDK4/6 inhibitors plus hormone therapies are better than

137 argeted therapy is significantly better than CDK4/6 inhibitors plus hormone therapies in terms of pro

138 We show that a combination of MEK and CDK4/6 inhibitors that target KRAS-directed oncogenic si

139 MEK or PI3K, can be used in combination with CDK4/6 inhibitors to reinforce or exploit senescence.

140 In parallel with clinical trials combining CDK4/6 inhibitors to treat HER2+ breast cancer, we sough

141 AC treatment we evaluated the interaction of CDK4/6 inhibitors with gemcitabine and taxanes that are

142 Thus, our findings indicate that CDK4/6 inhibitors, approved for a breast cancer subtype

143 CDK4/6 inhibitors, however, are not expected to cooperat

144 on the resistance mechanisms associated with CDK4/6 inhibitors, including cell cycle alterations and

145 Three different oral CDK4/6 inhibitors, palbociclib, ribociclib, and abemacic

146 ed drugs, afatinib and palbociclib (EGFR and CDK4/6 inhibitors, respectively) demonstrated synergy in

147 Accordingly, treatment with CDK4/6 inhibitors, which eventually results in restraini

148 ificantly associated with the sensitivity of CDK4/6 inhibitors.

149 rofile associated with positive responses to CDK4/6 inhibitors.

150 tumor types that are relatively resistant to CDK4/6 inhibitors.

151 ds to in vitro and in vivo susceptibility to CDK4/6 inhibitors.

152 al determinants of response to pharmacologic CDK4/6 inhibitors.

153 se that is refractory to clinically relevant CDK4/6 inhibitors.

154 n D1 expression and selective sensitivity to CDK4/6 inhibitors.

155 clin D1 axis as well as cancers resistant to CDK4/6 inhibitors.

156 sensitivity of ribociclib-resistant cells to CDK4/6 inhibitors.

157 roliferative and more prompted to respond to CDK4/6 inhibitors.

158 s of CDK6 and a more significant response to CDK4/6 inhibitors.

159 RK pathway enhanced the cytostatic effect of CDK4/6 inhibitors.

160 apeutic relevance of senescence induction by CDK4/6 inhibitors.

161 irradiation, and targeted therapies such as CDK4/6 inhibitors.

162 e neutropenia induced by treatment with dual CDK4/6 inhibitors.

163 ategy to potentiate the antitumor effects of CDK4/6 inhibitors.

164 olangiocarcinoma that confers sensitivity to CDK4/6 inhibitors.

165 ction point has been proposed to result from CDK4/6 initiating partial Rb phosphorylation to trigger

166 However, when CDK4/6 is activated relative to CDK2 remained incomplete

167 egulating cell cycle progression, inhibiting CDK4/6 is an attractive therapeutic strategy.

168 Combinatorial inhibition of MEK1/2 and CDK4/6 is currently undergoing clinical investigation in

169 nd downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in v

170 of the activity of the cell cycle-regulating CDK4/6 kinases and identifies MET/FAK as a tractable rou

171 8)F-CDKi was synthesized and assayed against CDK4/6 kinases.

172 Pharmacological or genetic inhibition of CDK4/6 or EZH2 abrogated psoriasis-related proinflammato

173 athway, but also proposes the repurposing of CDK4/6 or EZH2 inhibitors as a new therapeutic option fo

174 Importantly, topical application of CDK4/6 or EZH2 inhibitors on the skin was sufficient to

175 ugh HIF-2alpha transcriptionally induced the CDK4/6 partner cyclin D1, HIF-2alpha was not required fo

176 Delineation of the pathway revealed that CDK4/6 phosphorylated EZH2 in keratinocytes, thereby tri

177 While CDK4/6 represents a downstream target of both KRAS mutat

178 IF-2alpha was not required for the increased CDK4/6 requirement of VHL(-/-) ccRCC cells.

179 These results were further verified by CDK4/6 siRNA knockdown.

180 CDK4/6 targeting by miR-6883-5p and miR-149* could only

181 CDK4/6 targeting is a promising therapeutic strategy und

182 stress signals in G1 can rapidly inactivate CDK4/6 to return cells to quiescence but with reduced pr

183 mammalian target of rapamycin complex 1 and CDK4/6 via ALK3-mediated P-SMAD1/5 and p21 upregulation

184 In contrast, pharmacological inhibition of CDK4/6 yields a cooperative cytostatic effect in combina

185 tive of an improved biologic response to the CDK4/6(i) palbociclib, in combination with an aromatase

186 and cyclin-dependent kinase 4/6 inhibitors (CDK4/6(i)).

187 ctivity of cyclin-dependent kinases 4 and 6 (CDK4/6) and VHL inactivation in two species (human and D

188 Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and ar

189 Cyclin-dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle, and there

190 e identify cyclin-dependent kinases 4 and 6 (CDK4/6) as essential regulators of NETs and show that th

191 primarily targeted monomeric CDK4 and CDK6 (CDK4/6) in breast tumor cells.

192 treated with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and an aromatase inhibitor (AI), given

193 a radiolabeled cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for breast cancer imaging.

194 Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estro

195 ulation of cyclin-dependent kinases 4 and 6 (CDK4/6) is highly prevalent in cancer; yet, inhibitors a

196 Cyclin-dependent kinases 4 and 6 (CDK4/6) phosphorylate and inhibit retinoblastoma (RB) fa

197 tivation of cyclin-dependent kinase 4 and 6 (CDK4/6), rather than by the human papillomavirus (HPV).

198 ivating cyclin-dependent protein kinase 4/6 (CDK4/6).

199 e inhibition of cyclin-dependent kinase 4/6 (CDK4/6).

200 (PI3K) and/or cyclin-dependent kinases 4/6 (CDK4/6).

201 els, down-regulated the miR-34a target genes CDK4/6, and caused a cell cycle arrest in the G(1) phase

202 de genomic bases for the efficacy of mTORC1, CDK4/6, and PARP inhibitors in metastatic breast cancer.

203 Ds, which activate and confer specificity to CDK4/6, can compensate and proliferate.

204 degrader molecules capable of degrading both CDK4/6, or selectively degrading either CDK4 or CDK6.

205 n of resistance to the inhibition of MEK1/2, CDK4/6, or their combination in NRAS-mutant melanoma.

206 rt, cells first activate the kinase cyclin D-CDK4/6, which leads to eventual inactivation of the reti

207 In this study, CDK4/6-dependent and -resistant models were employed to

208 Moreover, we found a hyperactivation of the CDK4/6-EZH2 pathway in human and mouse psoriatic skin le

209 se/focal adhesion kinase (FAK) axis leads to CDK4/6-independent CDK2 activation, involving as critica

210 onal classes of cancer that may benefit from CDK4/6-inhibiting drugs such as abemaciclib.

211 their interaction is primarily dependent on CDK4/6-mediated serine-249/threonine-252 (S249/T252) pho

212 Abemaciclib, a CDK4/6-selective inhibitor, is currently in phase III st

213 Accordingly, we developed CDK4/6-targeted proteolysis-targeting chimeras (PROTACs)

214 maintained its potent targeting affinity to CDK4/6.

215 tivity was recently shown to be required for CDK4 activation, we proposed that proline-directed kinas

216 elanoma, a tumor that exhibits high rates of CDK4 activation.

217 that stoichiometric inhibition of cyclin D1-CDK4 activity by p21 controls the retinoblastoma (Rb) an

218 Specific inhibition of CDK4 activity by palbociclib blocked DREAM complex disas

219 t binding of phosphorylated p27 (phosp27) to CDK4 altered the kinase adenosine triphosphate site to p

220 While depleting CDK4 and 6 was sufficient to limit proliferation in spec

221 ociclib instead primarily targeted monomeric CDK4 and CDK6 (CDK4/6) in breast tumor cells.

222 using inhibitors of cyclin-dependent kinases CDK4 and CDK6 are effective in some cancer types and are

223 analysis identifies cyclin-dependent kinases CDK4 and CDK6 as regulators of metastasis through distin

224 capable of inducing selective degradation of CDK4 and CDK6 as tools to pharmacologically dissect thei

225 The cyclin-dependent kinases Cdk4 and Cdk6 form complexes with D-type cyclins to driv

226 Combining in vivo CRISPR-based CDK4 and CDK6 gene editing with pharmacologic inhibition

227 In this context, multiple inhibitors of CDK4 and CDK6 have been developed, including three small

228 nical models, we defined clear functions for CDK4 and CDK6 in facilitating tumor growth and progressi

229 resistance to tamoxifen, fulvestrant and the CDK4 and CDK6 inhibitor palbociclib.

230 50% of EACs contained sensitizing events for CDK4 and CDK6 inhibitors, which were highly correlated w

231 Inhibition of the cell-cycle kinases CDK4 and CDK6 is now part of the standard treatment in a

232 ve therapeutic effects and whether targeting CDK4 and CDK6 is sufficient to reactivate RB pathway act

233 Although the cyclin-dependent kinases CDK4 and CDK6 play fundamental roles in cancer, the spec

234 d inhibitors of the cyclin-dependent kinases CDK4 and CDK6 substantially improve progression-free sur

235 al CDKs (CDK7 and CDK9) and cell cycle CDKs (CDK4 and CDK6) as well.

236 eta-catenin alterations and cell-cycle-gene (CDK4 and CDK6) mutations.

237 Cyclin D dependent kinases (CDK4 and CDK6) regulate entry into S phase of the cell c

238 ical mediator of resistance to inhibition of CDK4 and CDK6.

239 inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6.

240 ath and tumour regression upon inhibition of CDK4 and CDK6.

241 as highly potent and selective inhibitors of CDK4 and CDK6.

242 s study, we established a connection between CDK4 and lysosomes, an emerging metabolic organelle cruc

243 nt structural rearrangements targeting TERT, CDK4 and MDM2.

244 o p21, by independently phosphorylating both CDK4 and p21.

245 1 protein abundance is regulated by cyclin D-CDK4 and the cullin 3-SPOP E3 ligase via proteasome-medi

246 pathway driven by cyclin-dependent kinase 4 (CDK4) and CDK6 and the methyltransferase EZH2 as a valid

247 nt cells, such as cyclin-dependent kinase 4 (CDK4) and CDK6, have attracted considerable interest as

248 Persistent CDK4 blockade decreased phosphorylation of tuberous scle

249 Ks could be activating kinases for cyclin D1-CDK4 bound to p21, by independently phosphorylating both

250 circumstances, p27 is associated with active CDK4, but no mechanism for activation has been described

251 ading to increased expression of EGFR, MAPK, CDK4, CDK2, CDK7, CCNE1 and CCNE2.

252 gh upregulation of p27 and downregulation of CDK4, CDK6, and cyclin D3.

253 d between treatment and expression levels of CDK4, CDK6, cyclin D1, and RB1.

254 e validate predicted resistance mutations in CDK4, CDK6, ERK2, EGFR and HER2.

255 Moreover, CDK4/CDK6 inhibition delays acquisition of resistance.

256 t target of NUP98-fusion proteins, proposing CDK4/CDK6 inhibitors as a new rational treatment option

257 it remains a reliable readout for effects of CDK4/CDK6 inhibitors on cell proliferation.

258 ce indicates that the anticancer activity of CDK4/CDK6 inhibitors results not only from their ability

259 These results indicate that the cyclin D1-CDK4 complex represents a potential selective therapeuti

260 Our data characterize phosp27-CDK4-CycD1 as an active Rb kinase that is refractory to

261 urprisingly, purified and endogenous phosp27-CDK4-CycD1 complexes were insensitive to the CDK4-target

262 ly activated CDK4 in complex with cyclin D1 (CDK4-CycD1).

263 nes revealed that A3B is not a substrate for CDK4-Cyclin D1 phosphorylation nor is its deaminase acti

264 onal expression of the cell cycle regulators Cdk4/cyclinD1, thus increasing neurogenesis.

265 cell cycle arrest mediated by the cyclin D1-CDK4 degradation pathway.

266 Cyclin D-Cyclin-Dependent Kinase 4 (CDK4)-dependent phosphorylation of p130 occurred during

267 found that A3B is capable of disrupting the CDK4-dependent nuclear import of Cyclin D1.

268 On the other hand, CDK4 directly regulated lysosomal function and was essen

269 luenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1

270 acted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2.

271 ber alterations, including amplifications in CDK4, FOXA1, and BCL11A.

272 e of the cell cycle regulators cyclin D2 and Cdk4 in a manner dependent on the signaling mediator Erk

273 y tyrosine kinases, allosterically activated CDK4 in complex with cyclin D1 (CDK4-CycD1).

274 , we uncovered a previously unknown role for CDK4 in lysosomal biology and propose a novel therapeuti

275 These findings uncover a novel function of CDK4 in lysosomal biology, which promotes cancer progres

276 id and preferential degradation of CDK6 over CDK4 in Ph+ ALL cells, and markedly suppress S-phase cel

277 In addition, sensitivity to CDK4 inhibition was dependent on RB and an intact DREAM

278 activation) and impaired lysosomal function (CDK4 inhibition), resulting in cell death and tumor regr

279 B knockout cells were partially resistant to CDK4 inhibition, RB and p130 double knockout cells were

280 cally vulnerable to cyclin D1 deficiency and CDK4 inhibition, suggesting that the obese/diabetic envi

281 sensitivity to palbociclib, an FDA-approved CDK4 inhibitor, which was effective in treating orthotop

282 sing an AMPK activator in combination with a CDK4 inhibitor.

283 Importantly, the use of CDK4 inhibitors in therapy is known to cause senescence

284 Cyclin-dependent kinase 4 (CDK4) is well-known for its role in regulating the cell

285 ine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity.

286 , Pdx1, MafA and Nkx6.1, but lower CCND1 and CDK4 levels, compared with Pdx1(+)/Ptf1a(-) lineage beta

287 d are associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1 and GAB2, indicating potential t

288 both CDK4/6, or selectively degrading either CDK4 or CDK6.

289 ologic inhibition or genetic inactivation of CDK4, other than retaining FLCN at the lysosomal surface

290 r BI-induced Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling, which, as we reported previously, i

291 On the one hand, CDK4 phosphorylated the tumor suppressor folliculin (FLC

292 These results unveil a CDK4-PIN1-p53-RS-c-Myc pathway as a novel mechanism for

293 r, the molecular signals leading to cyclin D/Cdk4/pRb activation following ischemic insult are presen

294 h, whereas expression of the closely related CDK4 protein is dispensable.

295 ion at the G1-S transition by inhibiting the CDK4/Rb pathway.

296 CDK4 regulated prometastatic inflammatory cytokine signa

297 Moreover, we report that CDK4 represses FAO through direct phosphorylation and in

298 Inhibition of CDK6 but not CDK4 resulted in defective DNA repair and increased DNA

299 CDK4-CycD1 complexes were insensitive to the CDK4-targeting drug palbociclib.

300 mTORC1 promoted metabolic reprogramming via CDK4 toward increased glycolysis while simultaneously in