ライフサイエンスコーパス: CDK4

1 neo-expression of cyclin-dependent kinase 4 (CDK4).

2 nisms underlying the metabolic regulation by CDK4.

3 nd survival of NSCLC cells, such as TERT and CDK4.

4 ng been thought of as a redundant homolog of CDK4.

5 DK6's kinase activity and is not shared with CDK4.

6 iated cell cycle-promoting kinases, CDK2 and CDK4.

7 ight specifically initiate the activation of CDK4.

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

9 a, driver mutations in NRAS and BRAF promote CDK4/6 activation, suggesting that inhibitors such as pa

10 molecular basis for the synergistic usage of CDK4/6 and Akt inhibitors in treating Rb-proficient canc

11 Inhibition of CDK4/6 and autophagy is also synergistic in other solid

12 arrest at G0/G1 phase and the alterations of CDK4/6 and Cyclin D1 triggered by simvastatin could be r

13 G0/G1 phase, suggested by downregulation of CDK4/6 and Cyclin D1.

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

15 tic proteins that associate with response to CDK4/6 and MEK inhibitors, and the development of a luci

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

17 Combined targeting of both CDK4/6 and PI3K triggered cancer cell apoptosis in vitro

18 16, resulting in universal activation of the CDK4/6 and Rb pathways.

19 CDK4/6 are targetable and the selective CDK4/6 inhibitor

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

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

22 Here we demonstrate that inhibition of CDK4/6 blocks breast tumour metastasis in the triple-neg

23 Small-molecule inhibitors of the CDK4/6 cell-cycle kinases have shown clinical efficacy i

24 inhibition resulted from bypass of cyclin D1-CDK4/6 dependency through selection of CCNE1 amplificati

25 It has also become clear, however, that CDK4/6 effectively counter cancer cell-intrinsic tumor s

26 Pharmacological inhibitors of CDK4/6 have shown significant activity against several s

27 Our data describe a function for CDK4/6 in immunity.

28 port a subset of cancers highly sensitive to CDK4/6 inhibition and characterized by various genomic a

29 ive breast cancer cells can adapt quickly to CDK4/6 inhibition and evade cytostasis, in part, via non

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

31 We demonstrate that CDK4/6 inhibition inhibits melanoma progression through

32 lanoma; however, the therapeutic efficacy of CDK4/6 inhibition remains to be critically evaluated.

33 tigations showed that acquired resistance to CDK4/6 inhibition resulted from bypass of cyclin D1-CDK4

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

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

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

37 nsitivity of 560 cell lines to the selective CDK4/6 inhibitor abemaciclib and have defined cancers wi

38 expression and thus reduces the response of CDK4/6 inhibitor in highly proliferative metastatic mela

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

40 defect was correlated with up-regulation of CDK4/6 inhibitor p15(INK4B) and induction of a p53-indep

41 sful example of this today is the use of the CDK4/6 inhibitor palbociclib combined with aromatase inh

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

43 signaling node that, when targeted using the CDK4/6 inhibitor palbociclib, defines overlap and diverg

44 ting mice with PD or a structurally distinct CDK4/6 inhibitor prior to radiation blocked proliferatio

45 The reduced ER/PR expression after CDK4/6 inhibitor resistance was additionally observed in

46 ted the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for

47 when downregulated, yield sensitivity to the CDK4/6 inhibitor ribociclib.

48 of serial biopsies from a clinical trial of CDK4/6 inhibitor treatment for breast cancer.

49 Notably, combining CDK4/6 inhibitor treatment with anti-PD-1 immunotherapy

50 earch terms "PD0332991," "palbociclib," and "CDK4/6 inhibitor" to find all published articles of inte

51 stone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or ABT-199 (BCL2 antagonist) synergist

52 CDK4/6 are targetable and the selective CDK4/6 inhibitor, palbociclib, was recently FDA approved

53 Palbociclib, a specific CDK4/6 inhibitor, rapidly induces cell cycle arrest with

54 tion with ribociclib or palbociclib, another CDK4/6 inhibitor, synergistically inhibited proliferatio

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

56 reporter system to determine the effects of CDK4/6 inhibitors alone and in combination with MEK inhi

57 However, the determinants of the response to CDK4/6 inhibitors alone and in combination with other ta

58 ively and temporally measure the efficacy of CDK4/6 inhibitors and determine the extent that CDK acti

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

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

61 In general, CDK4/6 inhibitors are cytostatic as monotherapy but demo

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

63 highlight a potentially valuable feature of CDK4/6 inhibitors as epigenetic modulators to facilitate

64 Mechanistically, the effects of CDK4/6 inhibitors both on tumour cells and on regulatory

65 id CDK6 overexpression mediate resistance to CDK4/6 inhibitors but it also led to reduced expression

66 we found that cells acquiring resistance to CDK4/6 inhibitors due to CCNE1 amplification could be re

67 The response to selective CDK4/6 inhibitors has been modest in multiple myeloma, p

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

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

70 Recently, CDK4/6 inhibitors have shown promising clinical activity

71 nsight into synthetic lethal interactions of CDK4/6 inhibitors in breast cancer for the development o

72 iple pharmaceutical companies currently test CDK4/6 inhibitors in combination with letrozole in indep

73 n-going and future clinical trials utilizing CDK4/6 inhibitors in cutaneous melanoma.

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

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

76 Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth-inhibitory effec

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

78 d other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arre

79 osphorylation by depleting cyclin D or using CDK4/6 inhibitors releases Rb-mediated mTORC2 suppressio

80 In vivo, CDK4/6 inhibitors sensitize patient-derived xenograft tu

81 Alternative mechanisms of resistance to CDK4/6 inhibitors such as loss of pRb and cyclin E1 over

82 anticancer efficacy and reduced toxicity of CDK4/6 inhibitors such as palbociclib and multi-CDK inhi

83 early adaptation and acquired resistance to CDK4/6 inhibitors that enable alternate means of S-phase

84 new class of highly specific ATP-competitive CDK4/6 inhibitors that induce reversible G1-phase cell-c

85 re, we describe the heterogeneous effects of CDK4/6 inhibitors, the expression of antiapoptotic prote

86 PI3K inhibitors could prevent resistance to CDK4/6 inhibitors, they failed to resensitize cells once

87 uch as mTOR inhibitors, PARP inhibitors, and CDK4/6 inhibitors.

88 e of the CDK4/6 target, phospho-Rb (pRb), to CDK4/6 inhibitors.

89 pathway in mediating acquired resistance to CDK4/6 inhibitors.

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

91 This is overcome using CDK4/6 inhibitors.

92 cient PDAC cells are inherently resistant to CDK4/6 inhibitors.

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

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

95 nsequently, dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of TSC2 phospho

96 we show that dual blockade of PI3Kalpha and CDK4/6 is synergistically effective against multiple RB1

97 substitution or with a specific inhibitor of CDK4/6 kinase blocked Her4-induced stabilization of MDMX

98 the US Food and Drug Administration-approved CDK4/6 kinase inhibitor palbociclib induces apoptosis of

99 314, a putative phosphorylation site for the CDK4/6 kinase.

100 Dysregulated activation of the CDK4/6 kinases is a hallmark of most mammary-derived car

101 hese defects, whereas inhibition of Cyclin D:CDK4/6 mitigated the effects of DYRK1A inhibition or los

102 The 3'UTR of CDK4/6 mRNAs are targeted by a family of miRNAs, which i

103 Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also

104 Therefore, we investigated the CDK4/6 pathway and responses to the CDK4/6-specific inhi

105 Targeted inhibition of CDK4/6 pathway by small-molecule inhibitors palbociclib

106 The CDK4/6 pathway is frequently dysregulated in cutaneous m

107 Cyclin D and CDK4/6 play a key role in cell-cycle progression by phos

108 be ineffective in some settings of acquired CDK4/6 resistance.

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

110 CDK6 expression and reduced response of the CDK4/6 target, phospho-Rb (pRb), to CDK4/6 inhibitors.

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

112 CDK4/6 targeting is a promising therapeutic strategy und

113 combination of cyclin-dependent kinase 4/6 (CDK4/6) and EGFR inhibitors prevents the emergence of re

114 d cyclin-dependent kinases (cdks) (d-cyclins cdk4/6) and the "late" cyclins and cdks (cyclin A/E and

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

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

117 ibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance t

118 Cyclin-dependent kinases 4 and 6 (CDK4/6) drive progression through the G1 stage of the ce

119 Cyclin-dependent kinases 4 and 6 (CDK4/6) in complex with D-type cyclins promote cell cycl

120 Inhibition of CDK4 and CDK6 (hereafter CDK4/6) in vivo increases PD-L1 protein levels by impedi

121 G1/S-regulating cyclin-dependent kinase 4/6 (CDK4/6) pathway is activated in parallel with renal cell

122 istance to cyclin-dependent kinases 4 and 6 (CDK4/6) small-molecule inhibitors in breast cancer arise

123 ve inhibitor of cyclin-dependent kinase 4/6 (CDK4/6), prevents radiation-induced lethal intestinal in

124 sence of a sensitizing agent directed toward CDK4/6, a kinase previously established to impede muscle

125 and cell cycle regulators CCND1, CCNE1, and CDK4/6, along with increases in the levels of tumor supp

126 , a triple combination of endocrine therapy, CDK4/6, and PI3K inhibition was more effective than pair

127 ono-phosphorylated Rb, generated by cyclin D:Cdk4/6, is the only Rb isoform in early G1 phase.

128 s activates the cell-cycle-dependent kinases CDK4/6, which have been considered as drug targets for m

129 tely eliminates the essential requirement of CDK4/6-cyclin D (CDK-4/CYD-1) in C. elegans.

130 re, we investigate the critical functions of CDK4/6-cyclin D kinases, starting from an unbiased scree

131 Our data identify FZR1 as a candidate CDK4/6-cyclin D substrate and point to an APC/C(FZR1) ac

132 Most human cancers contain overactive CDK4/6-cyclin D, and CDK4/6-specific inhibitors are prom

133 Overall, our study establishes the CDK4/6-DUB3 axis as an important regulatory mechanism of

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

135 y as an important determinant in response to CDK4/6-inhibitors.

136 deubiquitinase, DUB3, as a target of CDK4/6; CDK4/6-mediated activation of DUB3 is essential to deubi

137 The p16(INK4a)-Cyclin D-CDK4/6-pRb pathway is dysregulated in 90% of melanomas.

138 Dysregulation of the p16-cyclin D1-CDK4/6-Rb pathway occurs frequently in melanoma; however

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

140 ated the CDK4/6 pathway and responses to the CDK4/6-specific inhibitor palbociclib.

141 bypasses cell division arrest induced by the CDK4/6-specific inhibitor PD-0332991.

142 cers contain overactive CDK4/6-cyclin D, and CDK4/6-specific inhibitors are promising anti-cancer the

143 target genes and cyclin D2, the activator of CDK4/6/2.

144 e basis of immunohistochemical expression of CDK4/6/pRb (S780).

145 ntify a deubiquitinase, DUB3, as a target of CDK4/6; CDK4/6-mediated activation of DUB3 is essential

146 lation of p27 (pY88) is required to activate cdk4, acting as an "on/off switch." We identified two SH

147 t JNKs, but not ERK1/2 or CAK, can be direct CDK4-activating kinases for cyclin D-CDK4 complexes that

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

149 nfirmed the involvement of JNK2 in cyclin D1-CDK4 activation.

150 am regulators of ischemic neuronal death and Cdk4 activation.

151 as the distinctly regulated step determining CDK4 activation.

152 sensor provides sensitive means of comparing CDK4 activity between different melanoma cell lines and

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

154 a fluorescent peptide biosensor to quantify CDK4 activity in melanoma cell extracts, skin biopsies a

155 red an oncoprotein, responsible for cyclin D-cdk4 activity.

156 n p27 that modulate pY88, thereby modulating cdk4 activity.

157 However, the pathological significance of CDK4 amplicon in GBM formation remains incompletely unde

158 GTPase family, encoded by CENTG1 located in CDK4 amplicon.

159 mosome 12q13-q15 (Cyclin-dependent kinase 4 (CDK4) amplicon) is frequently observed in numerous human

160 red EGFR amplifications and one demonstrated CDK4 amplification, genes for which approved and investi

161 dedifferentiated liposarcomas (WD/DDLS) have CDK4 amplification.

162 y number variations (EGFR, PDGFRA, MDM4, and CDK4 amplification; PTEN, CDKN2A, NF1, and RB1 loss).

163 hyperactivation, associated with mutation of CDK4, amplification of Cyclin D or loss of p16(INK4a) le

164 sion, we examined whether dual inhibition of CDK4 and ARK5 kinases using ON123300 results in a better

165 Inhibition of CDK4 and CDK6 (hereafter CDK4/6) in vivo increases PD-L1

166 cell proliferation and enhanced activity of Cdk4 and Cdk6 and phosphorylation of Rb protein.

167 Inhibitors of CDK4 and CDK6 are currently being tested in clinical tri

168 t activation of the cyclin-dependent kinases CDK4 and CDK6 are essential and sufficient to impair sen

169 Cdk4 and Cdk6 are related protein kinases that bind d-ty

170 for the inhibitory effects of ClC-3 siRNA on CDK4 and CDK6 expression.

171 n the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was

172 The selective CDK4 and CDK6 inhibitor palbociclib inhibits growth and

173 ion of miR-6883-5p or miR-149* downregulated CDK4 and CDK6 levels in human colorectal cancer cells.

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

175 phases by up-regulation of the expression of CDK4 and CDK6 through suppression of p21 and p27 express

176 d their associated cyclin-dependent kinases (CDK4 and CDK6) are components of the core cell cycle mac

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

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

179 effects of ClC-3 siRNA on the expression of CDK4 and CDK6, but not on that of cyclin D1, indicating

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

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

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

183 other subgroups (P = 0.02), particularly in CDK4 and cyclin D1, and were less likely to have BRAF mu

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

185 alignment with their oncogenic activities by CDK4 and PIKE-A stably transfected in GBM cell lines.

186 1 protein abundance is regulated by cyclin D-CDK4 and the cullin 3-SPOP E3 ligase via proteasome-medi

187 -PCR demonstrated downregulation of CDK1 and CDK4 and upregulation of Hsp72.

188 ementary and orthogonal methods, we identify CDK4 and XPO1 as potential therapeutic targets in this c

189 Frequency of mutation in high (CDKN2A, CDK4, and BAP1) and intermediate (MITF) susceptibility g

190 well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa c

191 let-7 levels, decreases OCT4, HMGA1, CCNB1, CDK4, and Lin28A protein, decreases sphere formation, an

192 atment arms, whereas CNAs in MYC, ATM, CDK2, CDK4, and MDM2 had no prognostic value.

193 egulation of cell cycle modulators Cyclin D, CDK4, and phospho-Rb.

194 p19(INK4D), reduced levels of cyclin D1 and CDK4, and reduced phosphorylation of the retinoblastoma

195 downregulation of MIF, Hsp70, Hsp90beta, and CDK4, and upregulation of Hsp72.

196 Surprisingly, the two lobes of Cdk4 are completely separated with the beta4-beta5 sheet

197 Cyclin D and cyclin-dependent kinase 4 (cdk4) are overexpressed in a variety of tumors, but thei

198 sion led to upregulation of cyclins D1-3 and cdk4, as well as their nuclear translocation, all of whi

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

200 sites did not impair the phosphorylation of CDK4 by JNKs.

201 dult mice deficient for the Cyclin D partner CDK4 (Cdk4(-/-) mice) exhibit hypoplasia in the pituitar

202 mice expressing a mutant hyperactive form of CDK4 (CDK4(R24C)).

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

204 nts was sufficient to protect kinase clients CDK4, CDK6, CRAF and ERBB2 from depletion induced by sil

205 ic patients, including compounds that target CDK4/CDK6 (palbociclib, ribociclib, and abemaciclib), au

206 ggest selective and reversible inhibition of CDK4/CDK6 as an effective means to enhance Ara-C killing

207 In vivo, timely inhibition of CDK4/CDK6 by PD 0332991 and release profoundly suppresse

208 Targeting CDK4/CDK6 in combination with cytotoxic killing therefor

209 CDK4/CDK6 inhibition in vitro and in tumors in mice caus

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

211 through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1.

212 Inhibition of CDK4/CDK6 revealed proteasome-mediated Ki-67 degradation

213 By selective inhibition of CDK4/CDK6 with PD 0332991, which leads to early G1 arres

214 ntaining the stoichiometry between cyclin D1-CDK4 complex and p21 resulted in hyperphosphorylation of

215 lts suggest that activation of the cyclin D1-CDK4 complex by NGP-1 via maintaining the stoichiometry

216 determined that insulin activates the CCND3-CDK4 complex, which in turn phosphorylates insulin recep

217 we report here that elevated levels of CCND1-CDK4 complexes promoted the transit from G0 to G1 and sh

218 direct CDK4-activating kinases for cyclin D-CDK4 complexes that are inactivated by p21-mediated stab

219 Based on OncoPPi-derived STK11-CDK4 connectivity, we observe enhanced sensitivity of ST

220 n half-life and enhanced binding of HSP90 to CDK4, consistent with CDC37 promoting kinase loading ont

221 cted splice isoforms of several genes Banf1, Cdk4, Cryaa, Eif4g2, Pax6, and Rbm5.

222 Interestingly, CDK4-cyclin D1 does not phosphorylate Ser3291.

223 CDK4/Cyclin D kinase hyperactivation, associated with mu

224 on for other CDK/cyclin complexes, including CDK4/cyclin D1, which displays an alternative (open) pos

225 t an open<-->closed equilibrium may exist in CDK4/cyclin D1, with closed conformations resembling tha

226 ermined that white adipose tissue (WAT) from CDK4-deficient mice exhibits impaired lipogenesis and in

227 A global kinome analysis of CDK4-deficient mice following insulin stimulation reveal

228 melanoma cell lines and further responds to CDK4 downregulation by siRNA or small-molecule inhibitor

229 ited a specific requirement for CDK6 but not CDK4 expression, most likely because, in these cells, CD

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

231 CDKN2A and CDK4 genes were wild type.

232 The cyclin-dependent kinase 6 (CDK6) and CDK4 have redundant functions in regulating cell-cycle p

233 itate CDK7-dependent activation of p21-bound CDK4, however, mutation of these sites did not impair th

234 wild-type CDC37 overexpression by increasing CDK4-HSP90 association and CDK4 protein levels in cells.

235 wild-type CDC37 overexpression, it augmented CDK4-HSP90 complex formation.

236 By affording means of monitoring CDK4 hyperactivity consequent to cancer-associated molec

237 utility of (a) an in vitro model using hTERT/Cdk4 immortalized human bronchial epithelial cell lines

238 constitutively increased 5-20-fold in hTERT/CDK4-immortalized human bronchial epithelial cells (HBEC

239 The roles of CDK4 in the cell cycle have been extensively studied, bu

240 dy, we show that co-expression of PIKE-A and CDK4 in TP53/PTEN double knockout GBM mouse model additi

241 ticipation of the cyclin-dependent kinase 4 (CDK4) in adipose tissue biology.

242 lenced lung cancer cells to the FDA-approved CDK4 inhibitor palbociclib.

243 dulates pY88 and increases resistance to the cdk4 inhibitor PD 0332991.

244 ted in a 50-fold reduction in p15 (Cyclin D1/Cdk4 inhibitor).

245 domain blocks pY88 and acts as an endogenous cdk4 inhibitor, identifying a potentially targetable reg

246 ylatable AMPKalpha2 mutants, or the use of a CDK4 inhibitor, increased FAO rates in MEFs and myotubes

247 Moreover by enabling to monitor response to CDK4 inhibitors, this biosensor constitutes an attractiv

248 lls exposed to either DNA damaging agents or CDK4 inhibitors.

249 Lastly, we found that CDK4 interacted with and phosphorylated DNMT1 in vitro,

250 3-RS's nuclear translocation in HCC, whereas CDK4 interacts with p53-RS in the G1/S phase of the cell

251 These data suggest that CDK4 is a critical downstream target of MEN1-dependent t

252 Together, our results demonstrate that CDK4 is a major regulator of insulin signaling in WAT.

253 eviously showed that T172 phosphorylation of CDK4 is conditioned by an adjacent proline (P173), which

254 of CDK6: CDK6 but not its functional homolog CDK4 is found at the promoters of the FLT3 and PIM1 gene

255 Two mutant CDK4 isoforms (R24C, R24L) similarly stimulated T cell r

256 tron microscopy structure of the Hsp90-Cdc37-Cdk4 kinase complex.

257 Consistently, CDK4 knockdown in INS-1 insulinoma cells inhibited gluco

258 d clinical specimens, we show that cyclin D1/CDK4 mediate resistance to targeted therapy for HER2-pos

259 H1) trafficking and ZONAB (YBX3) function in Cdk4-mediated cell-cycle progression.

260 es PD-L1 protein levels by impeding cyclin D-CDK4-mediated phosphorylation of speckle-type POZ protei

261 ly, those neuroendocrine tissues affected in Cdk4(-/-) mice are the primary targets of tumorigenesis

262 Strikingly, Men1(+/-); Cdk4(-/-) mice did not develop any tumors, and their isl

263 In addition, Cdk4(-/-) mice have increased oxidative metabolism and e

264 Pituitaries of Men1(+/-); Cdk4(-/-) mice showed no signs of loss of heterozygosity

265 ice deficient for the Cyclin D partner CDK4 (Cdk4(-/-) mice) exhibit hypoplasia in the pituitary and

266 Inhibition of CDK4 mimicked these alterations in normal mice, but not

267 antly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial d

268 a-prone families (22 with germline CDKN2A or CDK4 mutations).

269 ctivation of CDKs, we examined the impact of Cdk4 or Cdk2 disruption on tumorigenesis in Men1(+/-) mi

270 Further, CCND1-CDK4 overexpression conferred a competitive advantage wi

271 phosphorylation and activation of cyclin D1-CDK4-p21 but not the activation of cyclin D3-CDK4 that i

272 tream of Rac1-cyclin D1/CDK6 and upstream of CDK4-PAK1 in the p115 RhoGEF-Rac1-NFATc1-cyclin D1-CDK6-

273 p115 RhoGEF-Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling axis is involved in the modulation o

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

275 y modulating Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling.

276 hat is sensitive to cyclin-dependent kinase (CDK4) perturbation.

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

278 ed constitutive expression of E6, Cyclin D1, CDK4, pRb, and Rb and induced the protein levels of p21

279 nstrated a functional role for the cyclin D1/Cdk4/pRb (retinoblastoma tumor suppressor protein) pathw

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

281 and the customary reference to the p16(INKA)/CDK4/pRB pathway may no longer be accurate; all PPs are

282 mulation through canonical activation of the CDK4/pRB pathway.

283 Among them, we verify that MAPK1, CDK1, CDK4, PRMT5, beta-catenin, and UbxD8 are directly ubiqui

284 This novel mechanism explains how CDK4 promotes anabolism by blocking catabolic processes

285 Here, we report that CDK4 promotes anaerobic glycolysis and represses fatty a

286 is activation of cyclin-dependent kinase 4 (CDK4), promoting progression of the cell cycle.

287 Overexpressing CDC37 increased CDK4 protein half-life and enhanced binding of HSP90 to

288 ion by increasing CDK4-HSP90 association and CDK4 protein levels in cells.

289 ession in human colon cancer cells increased CDK4 protein levels, which was negated upon CDC37 knockd

290 xpressing a mutant hyperactive form of CDK4 (CDK4(R24C)).

291 We identified T172 phosphorylation of CDK4 rather than cyclin D accumulation as the distinctly

292 mutations affecting the p16(INK4A)-cyclin D1-CDK4-Rb and p19(ARF)-Mdm2-p53 cell cycle pathways.

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

294 emonstrate that PGC1alpha is novel cyclin D1/CDK4 substrate.

295 CDK4-p21 but not the activation of cyclin D3-CDK4 that is mainly associated to p27.

296 enic mutations in cyclin-dependent kinase 4 (CDK4) that naturally occur in human melanoma.

297 litates cell cycle progression by modulating cdk4 through p27 Y phosphorylation.

298 ion or overexpression coordinately acts with CDK4 to drive GBM tumorigenesis.

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

300 dominantly localized in the nucleus, whereas CDK4 was almost exclusively cytoplasmic.