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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).
Exchange Factors
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
The first clear indication for the existence of an exchange promoting factor for p21ras was found in the yeast Saccharomyces cerevisiae. The cell division cycle gene CDC25 was shown to regulate the RAS/adenylate cyclase pathway in this organism.8-10 The CDC25 gene product is dispensable in cells containing an activated RAS allele such as RAS2 Gly12→Val or a RAS mutant with an increased rate of nucleotide exchange such as RAS2 Thr152→Ile. Also, mutationally activated alleles of CDC25 cause a phenotype similar to yeast with a genetically activated RAS/adenylate cyclase pathway. In S. cerevisiae this pathway is under the control of fermentable sugars such as glucose in the medium: addition of glucose causes cAMP levels in the cells to rise rapidly. Mutations in CDC25 can prevent this regulation. It, therefore, appears that CDC25 encodes an upstream regulator of RAS proteins.
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.
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.
Development of novel 9-O-substituted-13-octylberberine derivatives as potential anti-hepatocellular carcinoma agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Jichao Chen, Yiping Duan, Xiaoxuan Yu, Jiarou Zhong, Jing Bai, Nian-Guang Li, Zheying Zhu, Jinyi Xu
To determine whether 6k inhibited hepatoma cell proliferation by cell cycle regulation, the cell cycle distribution was analysed by flow cytometry after staining cellular DNA with propidium iodide (PI). As shown in Figure 2(A,B), 6k caused cell cycle arrest at G2/M phase in a dose-dependent manner. Treatment of HepG2 cells with 6k at concentrations from 0 to 1.0 μM increased the G2-phase cell percentages from 18.00% to 32.16%, while the total cell percentages of G1 and S phases decreased from 82.00% to 67.83% concomitantly. Then, the mechanism of 6k-induced cell cycle arrest in HepG2 cells were further explored. The suppression of cell cycle progression from G2 to M phase in eukaryotic cells has been suggested to be associated with expressions of several regulatory proteins including cdc25c, cdc2 and cyclin B124. As seen in Figure 2(C,D), 6k significantly promoted cdc25c phosphorylation, inhibited cdc2 kinase activation and reduced cyclin B1 binding in concentration-dependent manners. These results indicated that 6k blocked G2/M phase of the cell cycle possibly by regulating the expressions of p-cdc25c, cdc2 and cyclin B1.
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].