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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).
Regulation of Cell Functions
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
A homolog of the yeast cdc2 gene exists in vertebrates, including humans, and is involved in cell cycle control.314,315 Moreover, homologs of the fission yeast mitotic inducer cdc25 are present in vertebrate species and are represented by a family of protein phosphatases, termed CDC25A, -B, and -C, which exhibit dual specificity.316 The CDC25C protein phosphatase is implicated as a positive regulator of entry into mitosis, whereas CDC25A appears to be required for progression through the M phase of the cycle. The vertebrate CDC25 protein phosphatases regulate the activity of proteins associated with the regulation of the cell cycle, in particular, the activities of cdc2-related kinases. The cdc2 protein kinase is present in the cytoplasm and the nucleus of mouse FM3A cells, and its activity in the nuclear fraction increases in the G2/M phase of the cycle.317 Despite a constant level of cdc2 kinase in mouse fibroblasts, translation of the cdc2 protein is activated at the G1S transition and is inactivated at the G2/M boundary.318 The accumulation of newly synthesized cdc2 protein is accompanied by a concurrent mechanism of degradation, resulting in the old pool of cdc2 being largely replaced each round of the cell cycle. Expression of cdc2 mRNA and protein in quiescent young human and hamster fibroblasts is stimulated in culture by serum, and the stimulated cells go through DNA synthesis and mitosis. In contrast, serum stimulation of senescent cells does not result in increased cdc2 expression.319,320 The human senescent cells also exhibit a deficiency of cyclin A and cyclin B mRNA. These deficiencies may be relevant to the lack of DNA synthesis and mitosis in the senescent cells.
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
in S. cerevisiae the CDC25 protein is present in a very low amount, even when high copy number plasmids are expressed in protease-deficient strains.28,29 Discrepancies concerning the intracellular distribution of the product of overex-pressed CDC25 gene, may be due to the different yeast strains used and growth conditions. Jones et al.18 report that CDC25 is equally distributed in cell membrane and cytoplasm, whereas Garreau et al.28 and Vanoni et al.29 emphasize its tight association with the particulate fraction. How this association takes place is not yet clear. In the N terminal domain of CDC25, an SH3 motif can be recognized within residues 65 and 129.29 This consensus sequence is found in proteins associated with the membrane as part of the site responsible for the anchorage to the membrane.30 Only a small portion of the CDC25 gene product can be solubilized even with high concentrations of guanidinium-HCl or urea, suggesting that strong hydrophobic interactions are involved in its binding to the membrane. A transmembrane domain has been proposed in the hydrophobic region 1452 to 1473.20,31,32 Interestingly, deletion of residues 1255 to 1550 renders the CDC25 protein soluble.29 Many potential sites for N-glycosylation and one for O-glycosylation at the Thr/Ser rich amino terminus can be identified in the CDC25 sequence.33 This has suggested that the N terminal domain of CDC25 is, in part, secreted through the cell membrane and lies in the extracellular space.4,32 However, in a recent report no experimental evidence for glycosylation was found.29 The CDC25 sequence predicts seven to nine phosphorylation sites for cAMP-dependent protein kinase.20,33Figure 3 resumes some structural properties of the CDC25 gene product.
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].
Design, synthesis and biological evaluation of novel tetrahydrothieno [2,3-c]pyridine substitued benzoyl thiourea derivatives as PAK1 inhibitors in triple negative breast cancer
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Dahong Yao, Jian Huang, Jinhui Wang, Zhendan He, Jin Zhang
Subsequently, to detect the mechanism of 7j-induced cell cycle arrest in MDA-MB-231 cells, we firstly measured the expression of p-cdc2Tyr15 which always be inhibited when cells entry into G2/M cell cycle. As shown in Figure 6(A), 7j obviously increased p-cdc2Tyr15 expression which demonstrated the inhibition of cdc2. Since cdc25c could active cdc2 by inducing cdc2 dephosphorylation. We next investigated the expression level of cdc25c and cyclinB which is the regulatory subunit of cdc2. And we also detected the expression of Pin1 and NEDD8 which also involved in cell cycle regulation17,18. The results revealed that 7j could decrease the expression of cdc25c, cyclinB1, Pin1 and NEDD8 (Figure 6(B)). Next, the knockdown of PAK1 was performed to detect whether 7j induced G2/M cell cycle arrest via PAK1. After PAK1 knockdown, 7j almost did not affect the phosphorylation of p-cdc2 at Tyr15, and this confirmed that the increase of p-cdc2Tyr15 after 7j treatment was mainly induced by PAK1 inhibition (Figure 6(C)). Collectively, these results demonstrated that 7j induced G2/M cell cycle arrest via PAK1 regulated cdc25-cdc2 inhibition.
Radiation-induced G2/M arrest rarely occurred in glioblastoma stem-like cells
Published in International Journal of Radiation Biology, 2018
Junfeng Liu, Yu Liu, Tao Xie, Longjun Luo, Cheng Xu, Qinglei Gao, Lu Shen, Feng Wan, Ting Lei, Fei Ye
Thus, G2/M arrest was not subsequently induced by ATM/Chk1 pathway activation in GSLCs as their parental GDCs. To clarify the mechanisms of this difference between GSLCs and GDCs, we analyzed the expression of cell-cycle-related proteins using western blotting. The expression of Cdc25c was apparently higher in GSLCs than in GDCs and was almost unchanged after irradiation. Considering that Cdc25c is considered to be related to radioresistance (Zhao et al. 2012; Li et al. 2013), high expression of Cdc25c in GSLCs also indicates that GSLCs are more resistant to irradiation. Because the quantity of total Cdc25c protein in GSLCs is large, phosphorylated Cdc25c only accounts for a very small proportion of total protein: the remaining phosphatase Cdc25c remains sufficient to drive the cell cycle. This is one likely explanation for the inconsistency between activated ATM/Chk1 and G2/M arrest. Second, the expression of Cdc25c and Cdc2 was influenced by many other factors, including 14-3-3, Gadd45, p21, and Wee1 (Wang XW et al. 1999; Abbas and Dutta 2009). G2/M arrest was not only controlled by the ATM/Chk1 pathway after irradiation but was also regulated by these proteins, whereas the detailed mechanisms remain to be elucidated.