ライフサイエンスコーパス: p14ARF

1 vate the coding regions of both p16INK4a and p14ARF.

2 have been proposed to explain this effect of p14ARF.

3 from Ela to p53 is disrupted through loss of p14ARF.

4 53-independent tumor suppressor activity for p14ARF.

5 two distinct tumor suppressors, p16INK4a and p14ARF.

6 of 31 (52%) of the carcinomas methylated at p14ARF.

7 bility gene is CDKN2A, encoding p16INK4A and p14ARF.

8 NRAGE, repressing the tumor suppressor gene p14ARF.

9 echanisms governing the repressive action of p14ARF.

10 blasts, and a selection for loss of p16INK4A/p14ARF.

11 cumulation of p21cip1 in response to ectopic p14ARF.

12 gatively impact p16 to a greater extent than p14ARF.

13 ions were identified in the coding region of p14ARF.

14 ng treatment with adriamycin or induction of p14ARF.

15 th Adp53, even when cells express endogenous p14ARF.

16 ), intermediate frequencies at NORE1A (15%), p14ARF (15%), p16INK4a (10%), DAPK (11%) and CRBP1 (9%),

17 p14ARF aberrant methylation was not related to the prese

18 Mechanistically, P14ARF activated the TFPI2 promoter in a p53-independent

19 p14ARF activates p53 by binding and inhibiting HDM2, res

20 n human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades T

21 P14ARF activation in tumor cells delayed their ability t

22 mutation alone (P < .001), either p53 or p16/p14ARF alteration (P < .001), and stage (P < .01).

23 curs first, the common occurrence of p53 and p14ARF alterations suggests that p14ARF inactivation is

24 that an important tumor suppressor protein, p14ARF (alternative reading frame product of the INK4A l

25 Here we relate physical interactions between p14ARF and MDM2, as determined using synthetic peptides

26 p53 was associated with depletion or loss of p14ARF and p16 expression.

27 endent kinase inhibitor 2A (CDKN2A, encoding p14ARF and p16Ink4a) deletions in pediatric infiltrative

28 3K27me3, as well as EZH2, extends throughout p14ARF and p16INK4a, indicating that polycomb repression

29 nalysed and compared alterations of the p16, p14ARF and p53 genes in 38 primary non-small cell lung c

30 an inverse correlation was not found between p14ARF and p53 genetic alterations (P=0.18; Fisher Exact

31 ata are consistent with the current model of p14ARF and p53 interaction as a complex network rather t

32 mor suppression, bicistronic coexpression of p14ARF and p53 is superior to p53 alone.

33 lated in serine/threonine residues in a p53, p14ARF and p73-independent manner.

34 n at CASP8, CDH1, CDH13, DAPK, MGMT, NORE1A, p14ARF and RARB2 in primary Wilms' tumours and CASP8, CD

35 CDKN2A encodes p16 and p14ARF and therefore inactivation of this locus can disr

36 for MGMT, 19% for DAPK, 18% for ECAD, 8% for p14ARF, and 7% for GSTP1, whereas it was not seen in the

37 reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with

38 ed protein kinase (DAPK), E-cadherin (ECAD), p14ARF, and glutathione S-transferase P1 (GSTP1) in 107

39 vels of Mdm2 activity resulting from loss of p14ARF, and high levels of Mdm2 protein resulting from a

40 Homozygous deletion of p16/p14ARF, and p53 mutations were determined by fluorescent

41 ly a single lysine residue absent from human p14ARF, and substitution of arginine for lysine in mouse

42 p14ARF antagonizes MDM2-dependent p53 degradation.

43 y in clear cell, whereas hypermethylation of p14ARF, APC, or RASSF1A was more frequent in nonclear ce

44 ated tumor suppressor genes VHL, p16/CDKN2a, p14ARF, APC, RASSF1A, and Timp-3.

45 Alterations in p53 or p16/p14ARF are found in a fourth of ES cases and define a su

46 p14ARF (ARF) and topoisomerase I play central roles in c

47 haracterized function as a tumor suppressor, p14ARF (ARF) is a positive regulator of topoisomerase I

48 hibitor of anchorage-independent growth with p14ARF (ARF).

49 Here we identify loss of p14ARF as a mechanism that allows dl1520 replication in

50 iate analysis, alterations of p53 and/or p16/p14ARF as a single variable, was the most adverse progno

51 to be a novel tumor suppressor function for P14ARF as an inhibitor of tumor-induced angiogenesis.

52 copy number alterations in EGFR and CDKN2A/B/p14ARF as early events, and aberrations in PDGFRA and PT

53 ate analysis with alterations of p53 and p16/p14ARF as separate variables, both were significant (P <

54 53 through a direct or indirect induction of p14ARF as well as direct transcriptional coactivation of

55 n cancer cells may require that both p53 and p14ARF be supplied [corrected].

56 Shortly after irradiation, p14ARF binds p53 independently of MDM2.

57 Recent evidence has shown that P14ARF binds to MDM2 leading to an increased availabilit

58 eal, intriguingly, that the tumor suppressor p14ARF binds to this segment and may thus shift the conf

59 encodes two distinct proteins, p16INK4a and p14ARF, both of which are implicated in replicative sene

60 d phospho-Ser(15) p53 and p21 independent of p14ARF but dependent on ATM kinase.

61 se data support that epigenetic silencing of p14ARF by promoter hypermethylation is a key mechanism i

62 ere, we report that loss of tumor suppressor P14ARF can contribute to activating the clotting cascade

63 As nuclear pools of p53 decline, endogenous p14ARF co-immunoprecipitates with MDM2 and is localized

64 d in the present study suggest that Rad6-p53-p14ARF complex formation and p53 ubiquitin modification

65 ced p53 response showed that stable Rad6-p53-p14ARF complex formation is associated with a parallel i

66 Importantly, the tumor suppressor p14ARF compromises the Hdm2-YY1 interaction, which is im

67 dels, we demonstrated that the inhibition of p14ARF could suppress p53 aggregation and sensitize canc

68 BRCA1 does not stabilize p53 in p14ARF-deficient cells.

69 Six cases with p16/p14ARF deletion were also studied for co-deletion of the

70 s of p53, and eight cases (13.3%) showed p16/p14ARF deletion, including one case with both alteration

71 Jun NH2-terminal kinase (JNK), p300/CBP, and p14ARF during cell cycle progression.

72 The small basic protein p14ARF, encoded by one of the alternative transcripts fr

73 e data imply that the amino terminal half of p14ARF, encoded by the alternative first exon (exon 1bet

74 degradation, we studied the relationship of p14ARF epigenetic silencing to the expression and locali

75 Mutations that affect p14ARF exon 1beta exclusively are very rare.

76 the only mutations so far reported to affect p14ARF exon 1beta exclusively have been knockout mutatio

77 of five different germline mutations at the p14ARF exon 1beta splice donor site in melanoma pedigree

78 The results indicate that endogenous p14ARF expression may be insufficient to ensure efficien

79 ifespan showed loss of RAR-beta and p16INK4A/p14ARF expression, but retained functional wild-type p53

80 cooperation with down-regulation of p16INK4A/p14ARF expression, were necessary and sufficient to conv

81 us and that this can occur in the absence of p14ARF expression.

82 s with p16 inactivation also inactivated the p14ARF gene (12 with homozygous deletions extending into

83 HD was detected only at the CDKN2A (p16INK4a/p14ARF) gene at 9p21 and was observed in 4 of 46 cell li

84 The p14ARF-H2B tail interaction is functional, as the antago

85 This is unexpected because p14ARF has been reported to inhibit the ubiquitination o

86 p53 mutation, and homozygous deletion of p16/p14ARF have each been shown to be prognostically signifi

87 Although p14ARF hypermethylation was slightly overrepresented in

88 MDM2, whereas in a colorectal cell line with p14ARF hypermethylation-associated inactivation, MDM2 pr

89 e genomic status of the unique exon 1beta of p14ARF in 53 human cell lines and 86 primary non-small c

90 this gene may help clarify the exact role of p14ARF in melanoma predisposition.

91 sults thus reveal a hitherto unknown role of p14ARF in the regulation of chromatin transcription, as

92 tor 2A (CDKN2A) locus (encoding P16INK4A and P14ARF) in a large number of tumors within one subtype o

93 p53 tumor suppressor pathway genes (p21 and p14ARF) in normal unstressed cells but is dissociated fr

94 of p53 and p14ARF alterations suggests that p14ARF inactivation is not functionally equivalent to ab

95 f the tumors and nine of them (50%) harbored p14ARF inactivation.

96 P14ARF-induced expression of TIMP3 inhibited endothelial

97 hat degrade hAda3 but not p53 could abrogate p14ARF-induced growth arrest despite the presence of nor

98 bed the role of hAda3 and p53 acetylation in p14ARF-induced human mammary epithelial cell (MEC) senes

99 of hAda3 that binds p53 but not p300 blocked p14ARF-induced p53 acetylation and protected MECs from s

100 We demonstrate that p14ARF-induced senescence of human mammary epithelial ce

101 t p53 for degradation and protects MECs from p14ARF-induced senescence, inhibited p53 acetylation.

102 We show that FMN2 is increased upon p14ARF induction at both the mRNA and the protein level

103 We analyzed the effect of p14ARF induction on nucleolar protein dynamics using SIL

104 radiation, and this correlated with impaired p14ARF induction.

105 overexpression of a p53-positive regulator, p14ARF, inhibited MDM2-mediated p53 degradation and led

106 n or adriamycin (ADR) induces recruitment of p14ARF into Rad6-p53 complexes.

107 We demonstrate that the re-introduction of p14ARF into tumor cells with wild-type p53 suppresses re

108 n of the Mdm2-mediated degradation of p53 by p14ARF is associated with a decrease in the proportion o

109 We report that p14ARF is epigenetically inactivated in several colorect

110 s p53, it has been proposed that the loss of p14ARF is functionally equivalent to a p53 mutation.

111 The tumor suppressor activity of P14ARF is in part a result of its ability to prevent the

112 p14ARF is the alternate tumor suppressor product of the

113 y documented, little is known about specific p14ARF lesions and their consequences.

114 16 h, of serum starvation without changes in p14ARF levels, demonstrating a physiological increase in

115 However, the subsequent finding of P14ARF loss in conjunction with TP53 gene loss in some t

116 sphorylation on critical serine residues and p14ARF-mediated downregulation of murine double minute 2

117 s, in which PTEN activation in vivo requires p14ARF-mediated sumoylation of EGR1.

118 We found that P14ARF mediates antiangiogenic effects by upregulating e

119 p14ARF methylation appears in the context of an adjacent

120 equently observed in neoplasms with aberrant p14ARF methylation.

121 trated to result in aberrant splicing of the p14ARF mRNA, confirming their role in melanoma predispos

122 vity, newly described here, are repressed by p14ARF much more than by adriamycin.

123 , constitutes an essential step in tethering p14ARF near target promoters.

124 However, no point mutations in p14ARF not altering p16INK4a have been described in prim

125 Interestingly, p14ARF nucleolar localization during this response is ab

126 is functional, as the antagonistic effect of p14ARF on chromatin transcription is lost upon deletion

127 script, was also generated from frameshifted p14ARF or p16INK4a transcripts that were isolated from t

128 Cells deficient in p16 and either p14ARF or p53 became hypermotile in response to LN5' but

129 sor gene function for p14ARF suggesting that p14ARF or p53 inactivation may be functionally equivalen

130 ncy of p73 correlated positively with either p14ARF or p53 mutation or both (P = 0.01) in primary non

131 p14ARF overexpression increased the levels of Mdm2 but i

132 Here we have compared the effects of p14ARF overexpression on the in vivo ubiquitination of p

133 he tumor suppressor genes p15INK4B (CDKN2B), p14ARF, p16INK4A (CDKN2A), and the housekeeping gene met

134 e or more of the adenomatous polyposis coli, p14ARF, p16INK4a, or death associated protein-kinase tum

135 deling of the heterochromatic domains of the p14ARF/p16INK4a locus in T24 bladder cancer cells, reduc

136 In cells lacking p14ARF, p53 is induced, and components of the ATM and AT

137 strongly imply that the inactivation of the p14ARF-p53 pathway, either by the E6-mediated degradatio

138 ression of E2F-1 induces apoptosis by both a p14ARF-p53- and a p73-mediated pathway.

139 se results demonstrate that up-regulation of p14ARF paralleled with MDM2 inhibition contributes to p5

140 Because it is known that p14ARF prevents MDM2 nucleocytoplasmic shuttling and thu

141 mutated HLA-A11 gene product and the mutated p14ARF product were highly represented in the peripheral

142 We also studied the profile of p14ARF promoter hypermethylation in an extensive collect

143 Our results demonstrate that p14ARF promoter hypermethylation is frequent in colorect

144 M2 expression patterns revealed that lack of p14ARF promoter hypermethylation was associated with tum

145 In primary colorectal carcinomas, p14ARF promoter hypermethylation was found in 31 of 110

146 Cancer cell lines with an unmethylated p14ARF promoter showed strong nuclear expression of MDM2

147 The results show that in this setting, p14ARF promotes p53 accumulation by increasing p53 prote

148 The p14ARF protein is also a potent tumour suppressor that a

149 rlapping synthetic peptides derived from the p14ARF protein sequence and found that a peptide corresp

150 ze the significance of H2B deacetylation and p14ARF recruitment in establishing a repressive environm

151 was controlled by HDM2-SP1 interplay, where P14ARF relieved a dominant negative interaction of HDM2

152 f the two CDKN2A cognate transcripts-p16 and p14ARF, respectively.

153 P14ARF sensitized cells to anoikis; conversely, the TBX2

154 ponse, all 10 with alterations in p53 or p16/p14ARF showed a poor chemoresponse (P = .03).

155 ty to inhibit Mdm2-mediated p53 degradation, p14ARF signals through hAda3 to stimulate p53 acetylatio

156 Because p14ARF stabilizes p53, it has been proposed that the los

157 Recent data indicate that p14ARF suffers inactivation by promoter hypermethylation

158 putative tumor suppressor gene function for p14ARF suggesting that p14ARF or p53 inactivation may be

159 o the suggestion that it is p16INK4a and not p14ARF that plays the critical role in melanoma predispo

160 In addition we show that like p14ARF, the proteasome inhibitor MG132 can promote the a

161 the critical signaling pathways activated by P14ARF to prevent vascular microthrombosis triggered by

162 ript may be preferentially targeted over the p14ARF transcript as additional p53 pathway lesions are

163 gene product resulted in the isolation of a p14ARF transcript containing a 2-bp deletion in exon 2.

164 The p14ARF transcript of CDKN2A is clearly important in dise

165 ithin the frameshifted region of the deleted p14ARF transcript, was also generated from frameshifted

166 P14ARF transcriptionally upregulated TFPI2, a Kunitz-typ

167 mong malignant gliomas, 60%-80% show loss of P14ARF tumor suppressor activity due to somatic alterati

168 e report the biochemical characterization of p14ARF tumor suppressor as a transcriptional repressor t

169 ormin-2 (FMN2) protein as a component of the p14ARF tumor suppressor pathway.

170 associated with increased expression of the p14ARF tumor suppressor.

171 ay provide new insights into P53-independent P14ARF tumor-suppressive mechanisms that have implicatio

172 The p14ARF tumour suppressor has been shown to inhibit degra

173 ither wild-type or lacking lysine) and human p14ARF undergo N-terminal polyubiquitination, a process

174 oplasms and gliomas, aberrant methylation of p14ARF was a relatively common epigenetic event.

175 ith MDM2 inhibition, MDM2-inhibitory protein p14ARF was increased in MCF+FIR cells.

176 The deletion of p14ARF was inversely correlated with the loss of p53 in

177 hylation of other genes such as p16INK4a and p14ARF was not associated with either MGMT hypermethylat

178 demonstrated that the mRNA of p21, MDM2, and p14ARF was up-regulated.

179 gene expression in response to adriamycin or p14ARF, we found that most genes were regulated similarl

180 Homozygous deletions of p14ARF were detected in 12 of 53 (23%) cell lines and 16

181 E2F-1 of the human tumour-suppressor protein p14ARF, which neutralizes HDM2 (human homologue of MDM2)

182 in these cells, IPTG-dependent induction of p14ARF, which sequesters MDM2 away from p53, does not le

183 rst reports that describe the interaction of p14ARF with a protein besides HDM2, which may define a p

184 nthetic peptides and systematic deletions of p14ARF, with consequential effects on p53 stabilization

185 nsive genes and that the induction of p53 by p14ARF, with little phosphorylation, leads to substantia