Tyrosine Phosphatases as New Treatment Targets in Acute Myeloid Leukemia
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
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).
Exchange Factors
Juan Carlos Lacal, Frank McCormick in The ras Superfamily of GTPases, 2017
Recently, a gene has been discovered in S. cerevisiae that is functionally and structurally related to CDC25: this has been named SDC25.11 While this gene is not essential, the 3′ terminal part of it can suppress the requirement for CDC25. Furthermore, partially purified preparations of the protein encoded by the carboxyl terminal portion of the SDC25 gene can directly stimulate guanine nucleotide exchange on both S. cerevisiae RAS2 protein and human p21c-Ha-ras.12 In addition, overexpression of this protein fragment in mammalian cells can cause a considerable increase in the GTP/GDP ratio on p21ras, indicating that the SDC25 protein is causing activation of p21ras, presumably through stimulation of guanine nucleotide exchange.13 SDC25 encodes the only exchange factor that is active on mammalian p21ras whose primary structure is known at this time. The SDC25 and CDC25 gene products are discussed in more detail in the Chapter 26.
Irradiation-induced damage and the DNA damage response
Michael C. Joiner, Albert J. van der Kogel in Basic Clinical Radiobiology, 2018
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.
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
Activation of the ATM/Chk1 pathway could phosphorylate Cdc25c at Serine-216 (Ser-216) (Peng et al. 1997; Zhao et al. 2012; Xue et al. 2016). The protein phosphatase Cdc25c regulates entry into mitosis by activating the Cdc2/CyclinB1 kinase complex. At the onset of mitosis, Cdc2 is dephosphorylated by Cdc25c at Threonine-14 (Thr-14) and Tyrosine-15 (Tyr-15), the Cdc2/CyclinB complex translocates into the nucleus, and the cell-cycle progresses into M phase (Hutchins and Clarke 2004; Perdiguero and Nebreda 2004; Boutros et al. 2007). Cdc25c and Cdc2 are both critical regulators in G2/M transition and are modulated by many factors. Previous studies have suggested that activation of the ATM/Chk1 pathway could inhibit Cdc25c activation, thereby preventing dephosphorylation of Cdc2 and entry into mitosis, as well as cell-cycle arrest at the G2/M phase (De Souza et al. 2000; Sancar et al. 2004; Boutros et al. 2007). However, in our study, we found that the percentage of G2/M phase GSLC cells was unchanged after irradiation, although there was high expression of p-ATM and p-Chk1. For GDCs, G2/M arrest occurred at 12 h and 24 h after irradiation with 4 Gy or 8 Gy, and both ATM and Chk1 were activated after irradiation.
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.
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].
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