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TP53 increases the amount of CDKN1A. 958 / 1085
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"Unexpectedly, while Wip1 depletion increased DAXX phosphorylation both before and after DNA damage and increased p53 stability and transcriptional activity, knock-down of DAXX impacted neither p53 stabilization nor p53 mediated expression of Gadd45a, Noxa, Mdm2, p21, Puma, Sesn2, Tigar or Wip1."
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"Our results showed that p53 was mainly retained in the nucleus after RAMP knockdown, indicating that p53 functioned as a transcription factor to increase the expression of p21 (McKenzie et al, 1999; Jiang et al, 2001; Jing et al, 2007) and promoted apoptosis (Yonish-Rouach et al, 1991; Lowe et al, 1993; Tsao et al, 1999)."
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"Furthermore, the p53-independent upregulation of HDM2 by RSL1D1 also increased the protein levels of p21 and FOXO3a in RSL1D1-downregulated HCT116 cells (Fig. 2B and Supplementary Fig. S2A), which is consistent with the current opinion that HDM2 directly interacts with p21 and FOXO3a for ubiquitination [55–57], thereby negatively regulating the levels of these two proteins."
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"These results provide new evidence for an important function of serine 37 phosphorylation, clearly distinguish the pathways of p53 activation in response to ultraviolet radiation or DNA damage inflicted by adriamycin, and reveal that serine 15 is crucial to support the p53 mediated basal expression of p21."
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"The reported observation that hnRNPA2 knockdown results in a p53 independent increase of p21 levels and an inhibition of cell proliferation XREF_BIBR, similar as observed here in ACC BMS1 (p.R930H) fibroblasts, together with the results form the interaction analyses of the proteomic data that show the largest number of interactions to involve p21 and hnRNPA2B1 in ACC fibroblasts, suggest that the reduced protein levels of hnRNPA2B1 likely play a role in ACC pathogenesis."
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"Interestingly, expressions of p21 and Bax, both of which are directly regulated by p53 XREF_BIBR, were also enhanced, indicating that LNT inhibited S-180 tumor growth possibly through blocking cell proliferation and inducing cell apoptosis or cellular senescence via targeting p53."
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"These dual-labeled cells were treated with scrambled siRNA (si-Control) or siRNA targeting TP53 (si- TP53 ), the latter of which resulted in >90% knockdown of TP53 transcript and protein, as well as elimination of p53-dependent CDKN1A transcription in response to IR (Figure xref )."
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"Upregulation of p16 , in response to various stresses, leads to inhibition of cyclin-dependent kinases (CDKs) that prevent retinoblastoma protein (pRB) phosphorylation and inactivation, causing cell cycle arrest and senescence, whereas activation of p53 induces either growth arrest or apoptosis, in part, by inducing the expression of p21, which is another CDK inhibitor."
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"This tumorigenic function of Olig2 is correlated with its oppositional relationship to p53, where wild-type (WT) Olig2 and the triple phospho-mimetic (TPM) Olig2 (S10D/S13E/S14E) repress the irradiation-induced p53 activation and expression of Cdkn1a (also known as p21 ) [ xref ]."
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"Thus, while p53 has been shown to promote p21 and VEGF expression, differences in the degree to which these changes are induced by the polymorphism variants in adenoma cells lead to the G variant lowering expression of cell arrest gene p21 and increased expression of angiogenesis mediating VEGF, promoting adenoma growth through increased cell proliferation and vascularity in tumors arising in patients with the G variant."
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"Maintenance of the G2/M checkpoint activation partly relies on transcriptional regulation by p53 that induces transcription of the cell-cycle inhibitor p21 CIP1 and WAF1, and on expressions of 14-3-3s (a scaffold and signaling protein), PUMA (BCL2 binding component 3), BAX (BCL2 partner and apoptotic activator) and GADD45 (growth arrest and DNA-damage-inducible gene)."
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"This checkpoint control operated at the level of inhibition of the activity of Cdc2 and cyclin B and occurred by two mechanisms : (a) p53 mediated up-regulation of p21CIP and WAF1 expression and its association with Cdc2 and cyclin B; and (b) prevention of the dephosphorylation of tyrosine 15 of Cdc2."
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"Intriguingly, we found that the demethylase activity of JMJD2D is not required for JMJD2D to interact with p53 and inhibit p53-induced p21 and PUMA expression by using the demethylase-dead JMJD2D mutant (JMJD2D-S200M), excluding the possibility that JMJD2D inhibits p53 DNA binding ability through demethylating the lysine residues of p53."
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"This is in contrast to a previous study that did not observe stabilization of p53 protein in SET-KO mice: immunohistochemistry analysis of SET-KO embryos demonstrated that, although levels of p21, a gene activated by p53, increase, protein levels of p53 remain unchanged (Kon et al., 2019)."
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"Furthermore, while p53 activated by γ-irradiation induces the levels of p21 and MDM2, two classical p53 targets, in the intestinal epithelium, no obvious increase of the levels of p21 and MDM2 was observed in the tuft cells from mice with Tm and Nb infections or succinate treatment as determined by the IF staining (Fig. S4e)."
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"Consistently, knockdown of the transcription factor p53 in MDMs reduced the expression of p21 and significantly impaired the phagocytosis of MOLT4 cells without affecting MDM viability (Supplementary Fig. xref ), suggesting that the spontaneous phagocytosis of leukemia cells is under the control of p53-dependent p21 expression."
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"After DNA damage in G1 phase, a rapid destruction of Cdc25A blocks the activation of cycE and Cdk2 (the key complex in G1/S transitoin), inducing a transient cell cycle arrest that can only last for several hours; A sustainable cell cycle arrest is realized by nuclear p53 inducing the transcription of p21, a short lived protein that binds and inhibits both cycD and Cdk4 (the key complex in cell cycle entry) and cycE and ac-Cdk 2)."
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"It is well established that, following DNA damage by a genotoxic agent, activated TP53 transcriptionally induces expression of p21 (cyclin dependent kinase inhibitor 1A, CDKN1A) which in turn causes cell cycle arrest allowing for damaged DNA to be repaired before continuing the cell cycle."
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"P53 activates expression of p21 Cip1 protein resulting in inhibition of CDK complexes and cell cycle arrest at the G1/S phase.31 SET protein can directly bind to p53 and suppresses p53 activation by acetylation, therefore, promoting G1/S transition during the cell cycle.20 4.2 PP2A inhibition."
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"Geminin depletion induces DNA re-replication in cancer cells, regardless of the presence or absence of the tumor suppressor protein p53, but p53 +/+ cancer cells induce expression and phosphorylation of p53, as well as expression of the CDK specific inhibitor p21 whose transcription is p53 dependent [; XREF_FIG]."
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"XREF_BIBR Withaferin A - the active component of the medicinal plant Withania somnifera - is able to downregulate the expression of HPV E6 and E7 oncoproteins and to induce accumulation of p53 and increase levels of p21, causing cell cycle arrest and strong antitumoral effect in nude mice xenografts."
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"Importantly, activation of p21 mRNA (XREF_FIG) and cell cycle arrest (XREF_FIG) induced by Nutlin-3, an inhibitor of the p53 and Mdm2 interaction XREF_BIBR, is not affected by ATM knockdown, indicating that ATM is not generally required for the p53 dependent activation of p21 mRNA expression and cell cycle arrest and then, that the effect of ATM is upstream of p53 activation."
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"Whereas levels of p53, phosphoserine-15 p53, p21, ARF and Bcl-X (L) were increased in response to exogenous overexpression of activated DDR1, dominant negative DDR1 inhibited irradiation induced MAPK activation and p53, phosphoserine-15 p53, as well as induced p21 and DDR1 levels, suggesting that DDR1 functions in a feedforward loop to increase p53 levels and at least some of its effectors."
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"P53 directly modulates p21 gene expression; however, the mechanism that regulates p16 expression is, to date, incompletely understood although it involves polycomb group proteins EZH2, BMI1, CBX7 as well as TF ETS2, noncoding RNAs (ncRNAs), and general chromatin architectural changes 8, 9."
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"P53 increases the activation of p21 transcription, thereby facilitating cellular senescence.6 As a putative candidate for cancer treatment, p53 and p21 signaling exerts a potent effect on senescence in various digestive system tumors, including HCC,7 colorectal cancer,8 gastric cancer9 and pancreatic cancer.10 Circular RNAs (circRNAs) are a novel class of endogenous non coding RNAs."
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"In-depth research reveals that p53 induces aging through its downstream p21 and ROS; to be more specific, certain level and duration of ROS is the determinant of p53 initiating the p21 transcription, while the increased p21 expression can exert its transcription regulatory function through the interaction with the transcriptional coactivator p300, which does not rely on PCNA binding or CDK kinase inhibitory activity; induce PIG3 expression and thus induce elevated ROS in cells; and the elevated ROS can maintain long-term cell cycle arrest."
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"The genetic instability may be due to cells ' (1) inability to accumulate intranuclear wt p53 to a threshold level at which p53 upregulates the transcription of WAF1 and CIP1 and gadd45, resulting in the loss of cell cycle control and (2) inefficient repair of DNA damage caused by genotoxic agents."
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"In contrast, p21 mRNA levels were generally elevated in the tetraploid clones (XREF_SUPPLEMENTARY and g, available at Annals of Oncology online) and consistent with p21 being a transcriptional target of p53 [XREF_BIBR], siRNA mediated p53-knockdown eliminated p21 expression (XREF_SUPPLEMENTARY, available at Annals of Oncology online), confirming that p21 expression is driven by p53 in this system."
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"Moreover, by using western blot analysis, we determined that EA increased the protein expression of the p53 target proteins p21, p53 upregulated modulator of apoptosis (PUMA) [also known as Bcl-2-binding component3 (BBC3)] and Phorbol-12-myristate-13-acetate-induced protein 1 (NOXA)."
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"In the current study we tested the hypothesis that endogenous H2AX phosphorylation might be associated with constitutively low expression of p21 WAF1 (p21) and/or WIP1, both of which are transcriptionally activated by p53 and play major roles in the ATM-p53 pathway and maintenance of genomic stability."
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"RESULTS Treatment of the SW1736 and BHP7-13 cells with the PL-Pt(II) complex reduced cell proliferation in a dose-dependent manner, with an IC50 of 1.25 uM and 1.0 uM, respectively, and increased the cell fraction in G0/G1phase, inhibited p53, cyclin D1, promoted p27 and p21 expression, and significantly increased the sub-G1 fraction."
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"CDK2 is involved in the control of the cell cycle and is activated by interactions with cyclin E during the early stages of DNA synthesis to permit the G1-S transition and promote the transition from the S phase to mitosis.When cells are damaged, p53 induces the expression of p21 by recognizing disabled telomeres."
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"In conclusion, the present study demonstrated that the upregulation of P53 induced G1 phase arrest and apoptosis by upregulating P21 and Bax expressions; conversely, downregulating Bcl-2 and BIRC5 levels ultimately led to the suppressed growth of the HUVECs from preeclampsia pregnancies."
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"Cryptolepine induced DNA damage resulted in : (i) an increase in the phosphorylation of ATM and ATR, BRCA1, Chk1 and Chk2 and gammaH2AX; (ii) activation of p53 signaling cascade, including enhanced protein expressions of p16 and p21; (iii) downregulation of cyclin dependent kinases, cyclin D1, cyclin A, cyclin E and proteins involved in cell division (e.g., Cdc25a and Cdc25b) leading to cell cycle arrest at S-phase; and (iv) mitochondrial membrane potential was disrupted and cytochrome c released."
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"However, it has been demonstrated that p21 expression may also be activated by p53-independent pathways 21.However, considering the heterogeneity of breast cancer with its multiple genetic alterations and resistance to multiple treatment modalities 22, 23, targeting a single pathway by inhibiting the activity of one component would unlikely yield reasonable outcomes in the long run 24, 25."
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"Comparing p53 siRNA transfected A2780WT cells with scramble siRNA transfected cells we find in two independent experiments that p53 silencing reduces the increase in p53 and p21 Waf1 and Cip1 protein expression and Caspase 9 activity following 24 h exposure to Cisplatin (10 muM) from 56- to 4-fold (p53), 24- to 12-fold (p21 Waf1 and Cip1), and 29- to 4-fold (Caspase 9)."
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"Suppression of p53 expression by small interfering RNA in RT4 cells restored Cdc25C expression and down-regulated p21 and WAF1 expression, which allowed Cdc25C and CDK1 activation and then led to a G 2 -M arrest and an enhanced growth-inhibitory effect by flavokawain A. Consistently, flavokawain A also caused a pronounced CDK1 activation and G 2 -M arrest in p53 knockout but not in p53 wild-type HCT116 cells."
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"Depletion of p53 failed to restore p21 protein expression or reduce the sub-G1 population in Y14 depleted cells (XREF_SUPPLEMENTARY), reflecting diverse effects of Y14 depletion in human cells, and may also indicate species specific effect of Y14 depletion al least on alternative splicing of p53."
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"RESULTS Treatment of the SW1736 and BHP7-13 cells with the PL-Pt (II) complex reduced cell proliferation in a dose dependent manner, with an IC50 of 1.25 microM and 1.0 microM, respectively, and increased the cell fraction in G0/G1phase, inhibited p53, cyclin D1, promoted p27 and p21 expression, and significantly increased the sub-G1 fraction."
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"The exact molecular mechanisms allowing FOXO4 dependent p53 activation of p21 transcription are unknown but one can speculate that dual binding of p53 and FOXO4 at the promoter site of p21 can stimulate its transcription compared to a situation where a single transcription factor is available."
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"Numerous additional p53-independent factors induce
P21 expression (in various conditions), including: retinoic
acid, vitamin D, vitamin E, androgen, C/EBP-α, GAX, HOXA10, MAPK, nerve
growth factor, epidermal growth factor, progesterone, NeuroD, and MyoD1 [reviewed in
(Gartel and Tyner, 1999) and (Abbas and Dutta, 2009)]."
sparser
"Moreover, compared to p53 depleted cells, wild type p53 cells shows a reduced sensitivity to ferroptosis that requires p53-dependent expression of CDKN1A. However, CDKN1A-mediated cell cycle arrest is not involved in the inhibition of ferroptosis since treatment with CDK4/6 inhibitors is not able to prevent ferroptosis [ xref ]."
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"(1) Both p21 mRNA and P21 protein were overexpressed in human astrocytomas, the overexpression was related to cellular proliferation index, but was not related to P53 expression, suggesting there could be P53 independent pathway to induce the P21 expression, in addition, the overexpression of P21 alone appeared insufficient to suppress tumor growth, provided the participation of PCNA."
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"These findings suggest that a) in thymocytes, the apoptotic pathway is mostly p53 independent and the function of p21 as a negative regulator of the cell cycle must be redundant to other negative regulators, such as p16 and p27 which were abundantly detected in thymocytes and b) in some thymic epithelial cells, the p21 expression may be induced by p53, but in most of them seems to be p53 independent."
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"The mechanism involved in the block of cell cycle progression is activated by p53 that induces p21 expression, which in turn - by hindering pRb phosphorylation - blocks the activity of E2Fs transcription regulators and the consequent transit from G1 to S phase [XREF_BIBR, XREF_BIBR]."
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"There are several possibilities we can think of at the moment : 1) Knockdown INO80 destroyed the joint action between the INO80 and p53; 2) p53 may switch to co-activator after knockdown INO80 and activate the p21 gene transcription; 3) non p53 mediated mechanism may be involved in the transcription of p21 gene."
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"The p53 wild-type protein directly induces the expression of the p21 protein which binds to a variety of cyclin dependent kinases and inhibits their activity as well as regulates the repair of DNA and blocks its replication by inhibiting cell-cycle progression [XREF_BIBR, XREF_BIBR]."
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"This analysis demonstrated that p53 25,26 merely drives extremely low-level expression of p21, Noxa, and Puma but induces efficient expression of Bax comparable to wild-type p53, suggesting that p53 25,26 is severely impaired for transactivation of most but not all p53 target genes (XREF_FIG)."
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"For example, p53 induces CDKN1A expression to trigger reversible cell-cycle arrest upon serine depletion, which allows cancer cells to pause and manage oxidative stress thus leading to enhanced survival, whereas p53 deficient cells lacking the adaptive response display drastic cell death 11."
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"Furthermore, efficient stable knockdown of p53 in TPC-1 (TPC-1 sh-p53) cells effectively abrogated expression of p53, p21, MDM2, and PUMA in response to APG115 treatment, whereas stably transfected negative control shRNAi TPC-1 (TPC-1 sh-NC) cells did not cause concentration dependent upregulation of those proteins."
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"In this scenario, elevated p53 would initially promote the transcription of p21, a cell cycle inhibitor, to induce cell-cycle arrest and autophagy, but particularly severe or prolonged oxidative stress could eventually encourage apoptosis, through an imbalance in pro- and anti-apoptotic proteins, such as p53, Mdm2, Bax and Bcl-2 or Mtd and Mcl-1 XREF_BIBR."
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"These findings are consistent with animal studies showing an increased expression of p53 and p21 and Waf1 proteins in murine gastric lesions where the E-cadherin (CDH1) gene was conditionally deleted while concomitant knockdown of E-cadherin and p53 abrogates expression of p21, strongly increasing cell proliferation and gastric tumorigenesis in mice [XREF_BIBR]."
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"High-resolution chromatin immunoprecipitation assays (ChIP) demonstrate that p53 dependent activation of p21 (CIP1) transcription after DNA damage occurs concomitantly with changes in RNAP II phosphorylation status and recruitment of the elongation factors DSIF (DRB Sensitivity Inducing Factor), P-TEFb (Positive Transcription Elongation Factor b), TFIIH, TFIIF, and FACT (Facilitates Chromatin Transcription) to distinct regions of the p21 (CIP1) locus."
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"Functionally, p73, a family member of p53, activates transcription of p21- and p53 responsive genes, which participate in cell cycle control, DNA repair, and apoptosis and inhibits cell growth in a p53 like manner by inducing apoptosis or G1 cell cycle arrest XREF_BIBR, XREF_BIBR."
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"Previous studies in our laboratory have demonstrated that p400-dependent deposition of H2A.Z at the distal p53-binding site of the p21 promoter inhibits p53- dependent p21 transcription and thereby inhibits replicative senescence in primary human fibroblasts, but not in cells with deficient p53 xref ."
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"The G1/S checkpoint is enhanced by the induction of p21 transcription by p53, particularly in response to DNA damage, and the G2/M checkpoint is normally maintained by events downstream of p53, including CHK1 mediated phosphorylation of cdc25c and WEE1 mediated phosphorylation of cdc2."
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"This protein (p53) induces the transcription of p21 (by binding to two sites of its promoter), thereby causing the inhibition of cyclin B and Cdc2 complex activity and, eventually, cell cycle growth arrest at the G2/M phase [XREF_BIBR], which can further explain the slower proliferation rate of ALDH1B1 overexpressing cells."
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"A positive correlation between p53 and p21 expression was observed, however these samples with both positive immunoreactivity had no p53 mutation, suggesting the possibility that p53 may be wild-type and induce p21 expression, and/or p21 is likely to be induced by a p53 independent pathway."
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"In various studies, p53 independent induction of p21 expression by several agents including tissue plasminogen activator, dimethyl sulfoxide, trans-retinoic acid, butyrate, okadaic acid, epidermal growth factor and transforming growth factor-beta has been reported in cell lines expressing no or mutant p53 XREF_BIBR - XREF_BIBR."
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"On the one side, p53 promotes the expression of SAT1 (Qiu et al., 2020), and then increased SAT1 cooperates with ROS to lead to lipid peroxidation (Murphy 2016), further oxidizes PUFAs, and finally causes ferroptosis; on the other side, p53 directly inhibits the activity of DPP4 or induces the expression of CDKN1A/p21, to make it difficult for NOX1 to interact with DPP4 to form complexes, thus alleviating lipid peroxidation and ferroptosis (Tao et al., 2020)."
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"Previous studies have shown that both the P21 and P53 genes have the effect of inducing apoptosis to arrest the cell cycle ( xref ; xref ), and P53-mediated cell cycle arrest is mainly caused by P53-dependent transcription of P21 ( xref ). xref reported that miR-16-5p can increase the expression of P21, and can repress the proliferation of chicken myoblasts."
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"The observation that spontaneous p53 pulses do not activate p21 expression suggests that p53 is inactive as a transcriptional activator in non stressed conditions, and that transient low damage, like the one cells encounter during normal growth, is insufficient to convert it to its active form."
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"Although there was little p53 induction in the liver there was a strong p53 dependent p21 induction in the control mice, which was absent in the mice lacking p68, underscoring the requirement for p68 and indicating that only low levels of p53 induction are required to induce significant levels of p21."
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"Reverse-transcriptase PCR (RT-PCR) analysis revealed that the level of p21 CIP1 and WAF1 transcripts was low and did not decrease after deletion of Trp53, suggesting that p53 does not normally suppress fiber cell proliferation by increasing the level of p21 CIP1 and WAF1 in the lens (not shown)."
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"Furthermore, siRNA mediated knockdown of p53 mRNA and protein expression levels prevented ginkgolide B induced increases in the mRNA and protein levels of p21, and decreased subsequent apoptosis (XREF_FIG), whereas p21 knockdown blocked ginkgolide B triggered apoptosis in MCF-7 cells, but had no effect on the expression of p53 (data not shown)."
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"For example, treatment of HL-60 cells with 4-HNE (1muM) causes a p53 independent increase of p21 expression, RB dephosphorylation, progressive reduction in the amount of free E2F bound to DNA, and a relative increase in E2F complexes at higher molecular weights with repressive activity decrease of E2F complexes [XREF_BIBR], and decrease of cyclin D1, cyclin D2, and cyclin A [XREF_BIBR]."
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"Our previous work showed that repression of A3B expression by p53 involves a pathway in which p53 activation induces p21 expression, which inhibits CDK2/4/6 and so promotes recruitment of the transcriptional repressive E2F4/p107/p130-containing DREAM complex and concomitant displacement of the B-MYB transcriptional activation complex at the A3B gene [15]."
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"In contrast, a trend of upregulation of G2/M cell population was seen in ABT263 treatment groups compared with control and this trend was also observed in ABT263+AZD9291 compared with AZD9291 treatment groups, which could be associated with the downregulation of p53-dependent p21 expression as the synergistic mechanism of ABT263+AZD9291."