IndraLab
Statements
sparser
"While Chk2 activates multiple downstream targets in addition to p53, and the p53 protein may be activated through multiple post-transcriptional events [ xref ], the finding that CHEK2 mutations may substitute for TP53 mutations as a cause of chemo-resistance indicates Chk2 phosphorylation of the p53 protein to play a pivotal role executing cell death in response to anthracycline therapy in breast cancer."
sparser
"The phosphorylation of CHK2 and p53 was also increased by EEOM, indicating that activated CHK2 triggers p53 phosphorylation to increase the stability of p53. xref , xref However, EEOM did not show any big difference in the protein levels of Cdc25C. These results suggest that EEOM-mediated G2/M arrest occurs by inhibition of CDK/cyclin complex via p53-dependent p21 induction."
sparser
"Once activated, PIKKs phosphorylate large networks of proteins ( xref – xref ) including the downstream effector kinases Chk1 and Chk2 that phosphorylate p53 and other targets to arrest the cell cycle in response to damage, promote DNA repair, and promote programmed cell death pathways when damage is too extensive ( xref , xref – xref )."
sparser
"In response to UV, CHEK2 can also phosphorylate and stabilize the p53 protein, which in turn increases the transcription of p21 mRNA. xref However, hESCs do not display a G1/S checkpoint in response to all forms of DNA damage, such as that induced by IR. xref – xref Similar to hESCs, IPSCs also appear lack an IR-induced G1 checkpoint and instead arrest in the G2 phase of the cell cycle. xref "
reach
"MWNTs increase the expression of the base excision repair protein OGG1, the double strand break repair protein Rad 51, the phosphorylation of p53 by the checkpoint protein kinase ChK2, the phosphorylation of histone H2AX at serine 139, and SUMO modification of XRCC4 (in response to DNA double-strand breakage) in mouse embryonic stem cells."
sparser
"In this situation, CHK1 and CHK2 comparably phosphorylate p53 (usually at serines 15 and 20) to promote its stabilization. xref The phosphorylation of p53 enhances its interaction with transcriptional cofactors, which will ultimately activate target genes and responses, such as DNA repair, cell-cycle arrest, apoptosis (caspase-3), and senescence. xref "
sparser
"CHK2 is regarded as a tumour suppressor due to its role in apoptosis regulation with or without the involvement of ATM; upon phosphorylation, activated CHK2 phosphorylates the tumour suppressor gene P53 and multiple CDC25 molecules that negatively regulate kinase activation in a cyclin-dependent manner, which may provide insight into the potential mechanism of ITGB1-mediated radioresistance xref ."
reach
"XREF_BIBR, XREF_BIBR, XREF_BIBR The current study demonstrates that in cisplatin treated cells silencing TBX2 disrupts the ATM-CHK2-p53 axis, and based on our data we postulate that TBX2 is required for activating CHK2, which phosphorylates p53 leading to its stabilisation and its ability to activate downstream targets (XREF_FIG)."
sparser
"For example after DNA damage induced by the DNA topoisomerase II (Top2) inhibitor etoposide, Chk2 phosphorylates and activates the E2F-1 transcription factor that activates apoptotic pathways. xref Phosphorylation of p53 by Chk2 may lead to upregulation of Bax, an event also promoting apoptosis."
reach
"CHK2 is regarded as a tumour suppressor due to its role in apoptosis regulation with or without the involvement of ATM; upon phosphorylation, activated CHK2 phosphorylates the tumour suppressor gene P53 and multiple CDC25 molecules that negatively regulate kinase activation in a cyclin dependent manner, which may provide insight into the potential mechanism of ITGB1 mediated radioresistance XREF_BIBR."
rlimsp
"Although no definite conclusion should be drawn from a limited number of observation, the fact that Chk2 not only phosphorylates p53 but also phosphorylates other substrates such as Cdc25A and Cdc25C [54] and E2F1 in response to etoposide-induced DNA damage [61] may indicate that inactivation of redundant pathways could take place in parallel."
sparser
"The human homolog of the second S. pombe checkpoint kinase, Cds1 (CHK2/hCds1), phosphorylates tetrameric p53 but not monomeric p53 in vitro at sites similar to those phosphorylated by hCHK1 kinase, suggesting that both checkpoint kinases can play roles in regulating p53 after DNA damage."
reach
"For example, DNA damaging agents induce and activate p53 primarily through the induction of a number kinases, notably Ataxia telangiectasia mutated kinase (ATM), ataxia telangiectasia RAD3 related kinase (ATR), Chk1 and Chk2 which phosphorylate p53, MDM2, MDMX [XREF_BIBR - XREF_BIBR]."
sparser
"Furthermore, phosphorylation of checkpoint kinases CHK1 and CHK2 promotes the phosphorylation of p53 and enhances the stability of p53, hence causing activation of CASP3. xref Notably, CASP3 belongs to the caspase family member of 13 aspartate-specific cysteine proteases and promotes the formation of cleavage in cell apoptotic processes. xref Following the p53 signaling transduction, c-CASP3 cleaves PARP to induce cell apoptosis by producing nuclear DNA fragmentation. xref PARP is implicated in repairing single-strand DNA breaks and acts as a marker of cell apoptosis. xref Moreover, p53 degrades molecules involved in the migratory machinery for stabilizing junctions between cells, and hence the loss of p53 influences cell motility which further contributes to tumor metastatic potential. xref , xref Along with the activated p53 signaling pathway, JNK signaling was also activated by TF in this study."
reach
"The human homolog of the second S. pombe checkpoint kinase, Cds1 (CHK2 and hCds1), phosphorylates tetrameric p53 but not monomeric p53 in vitro at sites similar to those phosphorylated by hCHK1 kinase, suggesting that both checkpoint kinases can play roles in regulating p53 after DNA damage."
sparser
"PIKKs phosphorylate large networks of proteins[ xref – xref ]including the downstream effector kinases Chk1 and Chk2 that phosphorylate p53 and other targets to arrest the cell cycle in response to damage, promote DNA repair, and promote programmed cell death pathways when damage exceeds a threshold[ xref – xref ][ xref ]."
reach
"Although no definite conclusion should be drawn from a limited number of observation, the fact that Chk2 not only phosphorylates p53 but also phosphorylates other substrates such as Cdc25A and Cdc25C XREF_BIBR and E2F1 in response to etoposide induced DNA damage XREF_BIBR may indicate that inactivation of redundant pathways could take place in parallel."
reach
"In D816V-KIT MCs, activation of CHK2 by SPHK1-I mediated a depletion of CDC25c, a phosphatase needed for the removal of an inhibitory residue in CDK1 before entry into mitosis, and a downregulation in CDK1, which is needed for the induction of mitosis when complexed with cyclin B. Activated CHK2 also phosphorylated and stabilized p53, which then increased BAX but reduced BCL2 levels, resulting in cleavage and activation of the executioner CASP3."
reach
"PIKKs phosphorylate large networks of proteins [XREF_BIBR - XREF_BIBR] including the downstream effector kinases Chk1 and Chk2 that phosphorylate p53 and other targets to arrest the cell cycle in response to damage, promote DNA repair, and promote programmed cell death pathways when damage exceeds a threshold [XREF_BIBR - XREF_BIBR] [XREF_FIG]."
sparser
"Although no definite conclusion should be drawn from a limited number of observation, the fact that Chk2 not only phosphorylates p53 but also phosphorylates other substrates such as Cdc25A and Cdc25C xref and E2F1 in response to etoposide-induced DNA damage xref may indicate that inactivation of redundant pathways could take place in parallel."
sparser
"However, if DNA damage is present, ATM and checkpoint kinase 2 (CHK2) protein kinases phosphorylate p53, causing the dissociation of MDM2 and accumulation of p53, which then functions as a transcription factor inducing the synthesis of cyclin-dependent kinase inhibitor p21 (CDKN1A) and other targets."
reach
"PIKKs phosphorylate large networks of proteins including the downstream effector kinases Chk1 and Chk2 that phosphorylate p53 and other targets to arrest the cell cycle in response to damage, promote DNA repair, and promote programmed cell death pathways when damage exceeds a threshold [Figure 1]."
sparser
"Proteins such as H2AX, BRCA1, 53BP1, and MDC1, involved in the DNA damage cascade, are target substrates for ATM phosphorylation as well as the checkpoint proteins CHK1 and CHK2 that can phosphorylate p53, with downstream consequences on cell cycle progression and apoptosis [ xref ]."
sparser
"Activated CHK2 or CHK1 can phosphorylate p53 and latter induces DNA damage repair or initiates cell senescence. xref Activated p53 induces the transcription of p21, which blocks cell-cycle progression by inhibiting CDK2. xref MDM2 is an E3 ligase that binds p53 to cause its degradation while blocking this pathway by p14ARF represents another mechanism of p53 activation. xref "
reach
"Proteins such as H2AX, BRCA1, 53BP1, and MDC1, involved in the DNA damage cascade, are target substrates for ATM phosphorylation as well as the checkpoint proteins CHK1 and CHK2 that can phosphorylate p53, with downstream consequences on cell cycle progression and apoptosis [XREF_BIBR]."
rlimsp
"The current study demonstrates that in cisplatin-treated cells silencing TBX2 disrupts the ATM-CHK2-p53 axis, and based on our data we postulate that TBX2 is required for activating CHK2, which phosphorylates p53 leading to its stabilisation and its ability to activate downstream targets (Figure 6)."
sparser
"This is continued by the recruitment and activation of protein kinases, such as Chk1 and Chk2, which phosphorylate p53 [ xref ], activating the signaling cascade that leads to cell death by apoptosis [ xref , xref , xref , xref , xref , xref ] or necrosis [ xref , xref , xref ]."
reach
"While Chk2 activates multiple downstream targets in addition to p53, and the p53 protein may be activated through multiple post-transcriptional events [XREF_BIBR], the finding that CHEK2 mutations may substitute for TP53 mutations as a cause of chemo-resistance indicates Chk2 phosphorylation of the p53 protein to play a pivotal role executing cell death in response to anthracycline therapy in breast cancer."