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Tyrosine Phosphatases as New Treatment Targets in Acute Myeloid Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
I. Hubeek, K. Hoorweg, J. Cloos, Gertjan J. L. Kaspers
Cdc25 proteins belong to a high conserved family of DSPs that activate specific Cdk complexes (42). Cdks regulate progression through the cell division cycle and are kept inactive by the phosphorylation of two residues located within the ATP binding loop. Cdc25 phosphatases dephosphorylate these two residues when the Cdks are required for cell cycle progression (43). The expression and activity of Cdc25 proteins is regulated by many mechanisms, since they are involved in the complex mechanisms of the cell cycle. These regulating mechanisms include alternative exon splicing, phosporylation-dephosphorylation cycles, interaction with partner proteins, their intracellular localization, and cell cycle controlled degradation (24). In mammalian cells, three isoforms of Cdc25 are known Cdc25A, Cdc25B and Cdc25C. Two of them, Cdc25A and Cdc25B, are frequently overexpressed in cancers and are associated with poor prognosis. In AML, adhesion to fibronectin has been reported to upregulate Cdc25, leading to enhanced cell proliferation (44). The inhibition of Cdc25 could therefore be useful as a course of anticancer therapy. Another interesting target for cancer therapy that is currently under investigation is the DSP PTP MKP-1, which inactivates the JNK kinase and is overexpressed in many cancers (45).
Irradiation-induced damage and the DNA damage response
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Conchita Vens, Marianne Koritzinsky, Bradly G. Wouters
Cells that are in S phase at the time of irradiation demonstrate a dose-dependent reduction in the rate of DNA synthesis and as a result, the overall length of time that cells need to replicate their DNA substantially increases. This S-phase checkpoint is controlled by two highly related proteins known as CHK1 and CHK2 (Figure 2.6) (1). CHK1 and CHK2 are direct targets of ATR and ATM, respectively, and are activated by phosphorylation. They in turn phosphorylate the proteins CDC25A and CDC25C, which leads to their destruction or inactivation. CDC25A and CDC25C are phosphatases that keep CDK2 in its active dephosphorylated form. As a result, CHK1 and CHK2 activation by ATR and ATM results in an increase in the amount of phosphorylated CDK2 and thus slows progression through the S phase.
Properties of CDC25-Like Proteins
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
Andrea Parmeggiani, Michel-Yves Mistou, Eric Jacquet, Patrick Poullet, Jean-Bernard Créchet
Protein factors influencing the regeneration cycle of GTP-binding proteins are ubiquitous and have long since been known and well-characterized for quite a few systems such as protein biosynthesis, transport across membranes, and hormonal and sensorial response.10,11 Recent articles from different laboratories have described a number of GDSs for mammalian ras proteins.59,68,71,72 The preliminary characterization of their action shows commune features with that of the SDC25 C domain. It is not yet known but it is probable that these factors also share sequence similarities with the CDC25-like family. On the basis of these recent developments, the discovery of many more CDC25-like proteins controlling the most diverse pathways in the cell, can be expected in the time to come. Therefore, elucidation of the mechanisms regulating the functions of these GDS will represent the next major goal.
Expanding roles of cell cycle checkpoint inhibitors in radiation oncology
Published in International Journal of Radiation Biology, 2023
Sissel Hauge, Adrian Eek Mariampillai, Gro Elise Rødland, Lilli T. E. Bay, Helga B. Landsverk, Randi G. Syljuåsen
In addition to the p53-dependent G1 checkpoint, a delay can also be induced by suppressed CDK activity after ATM–CHK2-mediated degradation of CDC25 A (Bartek and Lukas 2001). As CDC25A degradation is initiated directly through protein modification, it represents a more rapid way of activating the G1 checkpoint than via p53-mediated transcription and protein synthesis (Bartek and Lukas 2001). Notably, in late G1 phase, very close to the G1/S border, ATR–CHK1 might also contribute to cause CDC25A degradation, and WEE1 might mediate Y15 phosphorylation on CDK2 and/or CDK1. Supporting this, both WEE1 and ATR inhibitors were shown to accelerate the S phase entry of non-irradiated cells (Bøe et al. 2018; Moiseeva et al. 2019). For cells that are close to the G1/S border at the time of irradiation, the WEE1, ATR and CHK1 kinases could therefore play a role in activating a G1 delay. However, these kinases are not expected to regulate the classical p53-dependent G1 checkpoint.
Screening and identification of key genes in imatinib-resistant chronic myelogenous leukemia cells: a bioinformatics study
Published in Hematology, 2021
Hong Zhang, Peiran Wang, Ting Song, Uwituze Laura Bonnette, Zhichao Zhang
In addition, we performed hierarchical clustering for others hub genes including HMMR, KIFC1, CDC25A, ZWINT, CDKN3, PTTG1. Results showed that these hub genes differentiated imatinib-resistant CML samples from imatinib-sensitive CML samples, and may be associated with the imatinib resistant of CML. HMMR, a receptor for hyaluronate-mediated motility (RHAMM), is an oncogene that leading to the neoplastic progression of human leukemias and solid tumors [47]. KIFC1 plays essential roles in the segregation of chromosomes in mitosis. It is overexpressed in breast cancers and may be associated with the docetaxel resistant of prostate cancer [48,49]. The protein kinase CDC25A acts as an activator of cyclin E-CDK2 that regulates the G1-S and G2-M transitions in colon cancer cells [50]. Previous studies found that the CDC25A is crucial for the proliferation of breast and lung cancer [51,52]. ZWINT is a centromere-complex component required for the mitotic spindle checkpoint and involved in the cell growth. Recent research has found that it can be a novel regulator of hepatocellular carcinoma by regulating cell-cycle-related proteins [53]. CDKN3 regulates mitosis, and high expression of CDKN3 is involved in the progression of ovarian cancer [54]. Overexpression of PTTG1 was found to promote the proliferation of several cancers, such as liver cancer, lung cancer and adrenocortical cancer [55–57].
Prexasertib: an investigational checkpoint kinase inhibitor for the treatment of high-grade serous ovarian cancer
Published in Expert Opinion on Investigational Drugs, 2020
Giulio Evangelisti, Fabio Barra, Melita Moioli, Paolo Sala, Sara Stigliani, Claudio Gustavino, Sergio Costantini, Simone Ferrero
The degradation of CDC25A and cytosolic sequestration of CDC25B-C prevents the activation of CDK1 and CDK2; this usually leads to the stops of the cell cycle for fixing DNA defects or activating the programmed cell death at G1 and G2 checkpoints [4547–48]. The WEE1 kinase contributes to regulating the activation of CDK1 negatively, thus determining the arrest of progression of the cell cycle at G2-M checkpoint, allowing to repair DNA defects [49]. Inhibition of WEE1 demonstrated to increases replication origin firing and double-stranded breaks accumulation, subsequently promoting premature entry into mitosis and mitotic catastrophe [5051–52]. AZD1775 (MK-1775) is the only WEE1 inhibitor tested as monotherapy and in combination with conventional CT for the treatment of HGSOC [53,54]. This drug showed encouraging antitumor activity in combination with carboplatin in the treatment of platinum-refractory or platinum-resistant HGSOC; moreover, it proved to be effective in treating HGSOC with TP53 mutation or with the defective function of DNA damage repairing system due to BRCA1-2 mutation [53,54].