Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ATM (ataxia-telangiectasia mutated) and ATR (ataxia-telangiectasia and Rad3-related) kinases respond to DNA damage by phosphorylating cellular target proteins that activate DNA repair pathways and cell cycle checkpoints in order to maintain genomic integrity. Here we show that the oncogenic p53-induced serine/threonine phosphatase, PPM1D (or Wip1), dephosphorylates two ATM/ATR targets, Chk1 and p53. PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair. These homeostatic functions may be partially responsible for the oncogenic effects of PPM1D when it is amplified and overexpressed in human tumors.
 ...
PMID:PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. 1587 Feb 57

The eukaryotic cell has evolved a sophisticated set of cell signaling pathways that respond to DNA damage and efficiently repair that damage, protecting the cell from deleterious mutations, genomic instability, and transformation into a cancerous state. The ATM and ATR serine/threonine kinases are key sensors and transducers of DNA damage signals through phosphorylation of an array of signaling molecules that mediate all aspects of the DNA damage response, including enforcement of cell cycle checkpoints and direct repair of damaged DNA. We have shown that a type 2C serine/threonine phosphatase, PPM1D (or Wip1), can reverse the phosphorylation status of ATM/ATR-phosphorylated proteins p53 and Chk1. This dephosphorylation of p53 and Chk1 by PPM1D may result in reduced functional activities and is accompanied by suppression of DNA damage-induced cell cycle checkpoints and some aspects of DNA repair. Because PPM1D is transcriptionally activated by p53 in response to DNA damage, PPM1D may serve as a critical component of a p53 negative feedback regulatory loop since it now appears that PPM1D can inhibit p53 activity by at least four different molecular mechanisms. This may explain why PPM1D is amplified and overexpressed in a subset of human breast cancers that invariably retain wild type p53 alleles. We hypothesize that PPM1D is a homeostatic regulator of the DNA damage response that returns the cell to a more normal unstressed state following repair of the damage.
 ...
PMID:Reversal of the ATM/ATR-mediated DNA damage response by the oncogenic phosphatase PPM1D. 1597 Jun 89

The tumor suppressor p53 is a transcription factor that responds to cellular stresses by initiating cell cycle arrest or apoptosis. One transcriptional target of p53 is Mdm2, an E3 ubiquitin ligase that interacts with p53 to promote its proteasomal degradation in a negative feedback regulatory loop. Here we show that the wild-type p53-induced phosphatase 1 (Wip1), or PPM1D, downregulates p53 protein levels by stabilizing Mdm2 and facilitating its access to p53. Wip1 interacts with and dephosphorylates Mdm2 at serine 395, a site phosphorylated by the ATM kinase. Dephosphorylated Mdm2 has increased stability and affinity for p53, facilitating p53 ubiquitination and degradation. Thus, Wip1 acts as a gatekeeper in the Mdm2-p53 regulatory loop by stabilizing Mdm2 and promoting Mdm2-mediated proteolysis of p53.
 ...
PMID:The Wip1 Phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop. 1793 59

The wild-type p53-induced phosphatase Wip1 (PP2Cdelta or PPM1D) is a member of the protein phosphatase 2C (PP2C) family and controls cell cycle checkpoints in response to DNA damage. p38 MAPK and ATM were identified as physiological substrates of Wip1, and we previously reported a substrate motif that was defined using variants of the p38(180pT 182pY) diphosphorylated peptide, TDDEMpTGpYVAT. However, the substrate recognition motifs for Wip1 have not been fully defined as the sequences surrounding the targeted residues in ATM and p38 MAPK appear to be unrelated. Using a recombinant human Wip1 catalytic domain (rWip1), in this study we measured the kinetic parameters for variants of the ATM(1981pS) phosphopeptide, AFEEGpSQSTTI. We found that rWip1 dephosphorylates phosphoserine and phosphothreonine in the p(S/T)Q motif, which is an essential requirement for substrate recognition. In addition, acidic, hydrophobic, or aromatic amino acids surrounding the p(S/T)Q sequence have a positive influence, while basic amino acids have a negative influence on substrate dephosphorylation. The kinetic constants allow discrimination between true substrates and nonsubstrates of Wip1, and we identified several new putative substrates that include HDM2, SMC1A, ATR, and Wip1 itself. A three-dimensional molecular model of Wip1 with a bound substrate peptide and site-directed mutagenesis analyses suggested that the important residues for ATM(1981pS) substrate recognition are similar but not identical to those for the p38(180pT 182pY) substrate. Results from this study should be useful for predicting new physiological substrates that may be regulated by Wip1 and for developing selective anticancer drugs.
 ...
PMID:The Wip1 phosphatase PPM1D dephosphorylates SQ/TQ motifs in checkpoint substrates phosphorylated by PI3K-like kinases. 1793 84

The Wild-type p53-induced phosphatase 1, Wip1 (or PPM1D), is unusual in that it is a serine/threonine phosphatase with oncogenic activity. A member of the type 2C phosphatases (PP2Cdelta), Wip1 has been shown to be amplified and overexpressed in multiple human cancer types, including breast and ovarian carcinomas. In rodent primary fibroblast transformation assays, Wip1 cooperates with known oncogenes to induce transformed foci. The recent identification of target proteins that are dephosphorylated by Wip1 has provided mechanistic insights into its oncogenic functions. Wip1 acts as a homeostatic regulator of the DNA damage response by dephosphorylating proteins that are substrates of both ATM and ATR, important DNA damage sensor kinases. Wip1 also suppresses the activity of multiple tumor suppressors, including p53, ATM, p16(INK4a) and ARF. We present evidence that the suppression of p53, p38 MAP kinase, and ATM/ATR signaling pathways by Wip1 are important components of its oncogenicity when it is amplified and overexpressed in human cancers.
 ...
PMID:The type 2C phosphatase Wip1: an oncogenic regulator of tumor suppressor and DNA damage response pathways. 1826 45

The p53 tumor suppressor is essential in maintaining genomic integrity in response to cellular stresses. In response to DNA damage, p53 is activated and stabilized largely through post-translational modifications, including phosphorylation by DNA damage responsive kinases such as ATM and ATR. Activated p53 transactivates a battery of genes that can mediate either cell cycle arrest or apoptosis. In those instances where p53 facilitates cell cycle arrest, a means to return the cell to a pre-stress state with low p53 levels is important. The E3 ubiquitin ligase Mdm2 is one p53 transcriptional target that accumulates after damage and promotes p53 ubiquitination and degradation. Thus, p53 and Mdm2 form a critical negative feedback regulatory loop that helps to maintain appropriate p53 levels in the presence or absence of stress. We propose here that Wip1 (Wildtype p53-Induced Phosphatase 1), also known as PPM1D, plays an important role in the p53-Mdm2 autoregulatory loop. We have recently shown that Wip1, also a p53 target gene, dephosphorylates Mdm2 at Ser395 (an ATM target site), resulting in stabilization of Mdm2, enhanced Mdm2-p53 binding, and enhanced ubiquitination of p53 by Mdm2. Thus, Wip1 facilitates Mdm2-mediated degradation of p53. The p53 inhibitory role of Wip1 implicates it as a potential oncogene and indeed Wip1 is amplified and overexpressed in a number of human cancers. Wip1 may inhibit p53 signaling by multiple mechanisms, but our data suggests that its largest effects are due to dephosphorylation of Mdm2.
 ...
PMID:The Wip1 phosphatase and Mdm2: cracking the "Wip" on p53 stability. 1833 94

The oncogenic Wip1 phosphatase (PPM1D) is induced upon DNA damage in a p53-dependent manner and is required for inactivation or suppression of DNA damage-induced cell cycle checkpoint arrest and of apoptosis by dephosphorylating and inactivating phosphorylated Chk2, Chk1, and ATM kinases. It has been reported that arsenic trioxide (ATO), a potent cancer chemotherapeutic agent, in particular for acute promyelocytic leukemia, activates the Chk2/p53 pathway, leading to apoptosis. ATO is also known to activate the p38 MAPK/p53 pathway. Here we show that phosphatase activities of purified Wip1 toward phosphorylated Chk2 and p38 in vitro are inhibited by ATO in a dose-dependent manner. Furthermore, DNA damage-induced phosphorylation of Chk2 and p38 in cultured cells is suppressed by ectopic expression of Wip1, and this Wip1-mediated suppression can be restored by the presence of ATO. We also show that treatment of acute promyelocytic leukemia cells with ATO resulted in induction of phosphorylation and activation of Chk2 and p38 MAPK, which are required for ATO-induced apoptosis. Importantly, this ATO-induced activation of Chk2/p53 and p38 MAPK/p53 apoptotic pathways can be enhanced by siRNA-mediated suppression of Wip1 expression, further indicating that ATO inhibits Wip1 phosphatase in vivo. These results exemplify that Wip1 is a direct molecular target of ATO.
 ...
PMID:Arsenic trioxide augments Chk2/p53-mediated apoptosis by inhibiting oncogenic Wip1 phosphatase. 1848 88

MdmX and Mdm2 regulate p53 tumor suppressor functions by controlling p53 transcriptional activity and/or stability in cells exposed to DNA damage. Accumulating evidence indicates that ATM-mediated phosphorylation and degradation of Mdm2 and MdmX may be the initial driving force that induces p53 activity during the early phase of the DNA damage response. We have recently determined that a novel protein phosphatase, Wip1 (or PPM1D), contributes to p53 regulation by dephosphorylating Mdm2 to close the p53 activation loop initiated by the ATM/ATR kinases. In the present study, we determine that Wip1 directly dephosphorylates MdmX at the ATM-targeted Ser403 and indirectly suppresses phosphorylation of MdmX at Ser342 and Ser367. Wip1 inhibits the DNA damage-induced ubiquitination and degradation of MdmX, leading to the stabilization of MdmX and reduction of p53 activities. Our data suggest that Wip1 is an important component in the ATM-p53-MdmX regulatory loop.
 ...
PMID:Phosphorylation and degradation of MdmX is inhibited by Wip1 phosphatase in the DNA damage response. 1980 70

The PP2C family serine/threonine phosphatase WIP1 is characterized by distinctive oncogenic properties mediated by inhibitory functions on several tumor suppressor pathways, including ATM, CHK2, p38MAPK and p53. PPM1D, the gene encoding WIP1, is aberrantly amplified in different types of human primary cancers, and its deletion in mice results in a profound tumor-resistant phenotype. Numerous downstream targets of WIP1 have been identified, and genetic studies confirm that some play a part in tumorigenesis. Recent evidence highlights a new role for WIP1 in the regulation of a cell-autonomous decline in proliferation of certain self-renewing cell types, including pancreatic beta-cells, with advancing age. These emerging functions of WIP1 make it a potent therapeutic target against cancer and aging.
 ...
PMID:WIP1 phosphatase at the crossroads of cancer and aging. 1987 49

The checkpoint kinase Chk2 is an effector component of the ATM-dependent DNA damage response (DDR) pathway. The activation of Chk2 by genotoxic stress involves its phosphorylation on T68 by ATM and additional auto/transphosphorylations. Here we demonstrate that in unperturbed cells, chemical inhibition of Chk2 by VRX0466617 (VRX) enhances the phosphorylation of Chk2-T68 throughout the cell cycle phases. This event, dependent on the presence of ATM and catalytically functional Chk2, is not consequential to DNA damage, as neither gamma-H2AX nuclear foci nor increased ATM activation is detected in VRX-treated cells, suggesting the involvement of other regulatory proteins. As serine/threonine protein phosphatases (PPs) regulate the phosphorylation and deactivation of proteins of the DDR pathway, we analyzed their role in phospho-T68-Chk2 regulation. We found that intracellular inhibition of PP1 and PP2A-like activities by okadaic acid markedly raised the accumulation of Chk2-pT68 without DNA damage induction, and this phenomenon was also seen when PP1-C, PP2A-C, and Wip1/PPM1D were simultaneously knockdown by siRNA. Altogether, these data indicate a novel mechanism in undamaged cells where PPs function to maintain the balance between ATM and its direct substrate Chk2 through a regulatory circuit.
 ...
PMID:A protein phosphatase feedback mechanism regulates the basal phosphorylation of Chk2 kinase in the absence of DNA damage. 2059 67


1 2 3 Next >>