China
Africa
Explore chapters and articles related to this topic
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
The cdc2 protein kinase is a key regulator of the eukaryotic cell cycle, and the cdc2 phosphorylation state varies according to the different phases of the cell cycle.325 Four major sites of cdc2 protein phosphorylation are present in chicken cells: Thr-14, Tyr-15, Thr-161, and Ser-277. These residues are highly conserved in evolution. Thr-14 and Tyr-15 are phosphorylated maximally during G2 and are abruptly dephosphorylated at the G2/M transition. Phosphorylation of the Thr-14 and Tyr-15 residues inhibits cdc2 kinase activity. A specific type of human phosphatase, cdc25B, is expressed at the G2/M boundary of the cycle and leads to the activation of the human cdc2 kinase by dephosphorylating both the Thr-14 and Tyr-15 cdc2 residues.326 Thr-161 phosphorylation is required for cdc2 interaction with cyclin and its function during the cell cycle,327 and dephosphorylation of Thr-161 is required for cdc2 protein kinase inactivation and normal anaphase.328 Ser-277 dephosphorylation of the cdc2 protein peaks during G1 and drops markedly as cells progress through the S phase of the cycle.
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].
Inhibition mechanism of naphthylphenylamine derivatives acting on the CDC25B dual phosphatase and analysis of the molecular processes involved in the high cytotoxicity exerted by one selected derivative in melanoma cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Federica Aliotta, Rosarita Nasso, Rosario Rullo, Alessandro Arcucci, Angelica Avagliano, Martina Simonetti, Gennaro Sanità, Mariorosario Masullo, Antonio Lavecchia, Maria Rosaria Ruocco, Emmanuele De Vendittis
Although the different types of cancer are characterised by a great heterogeneity, one of the main and more common traits is represented by a deregulation of the cell cycle. Indeed, many (chemo)therapeutic agents act on cell cycle through the inhibition of macromolecules involved in the regulation of cell cycle progression1. Cyclin-dependent kinases (CDKs) are pivotal regulators of cell cycle; they are active when linked to specific cyclins and their regulation involves the binding to negative modulators and/or the occurrence of phosphorylation/dephosphorylation events1,2. In particular, the CDK•cyclin complexes are inactivated through the phosphorylation of specific residues of threonine and tyrosine in the CDK subunit. The control of cell cycle progression also involves the action of CDC25 enzymes, catalysing the removal of the inhibitory phosphate groups in CDKs3. Indeed, the dephosphorylation of CDK threonine and tyrosine residues is catalysed by CDC25 dual phosphatases, highly conserved and present in all eukaryotes, except plants4–6. There are three forms of CDC25 enzymes, CDC25A, –B and –C. CDC25A is mainly involved in the regulation of both G1/S and G2/M transitions. In particular, in G1 phase CDC25A dephosphorylates and thus activates CDK4 and CDK6, and then, in late G1 phase promotes the G1/S transition, by dephosphorylating and activating the CDK2•cyclin A and CDK2•cyclin E complexes5. Furthermore, CDC25A also activates the CDK1•cyclin B complex, thus contributing to the G2/M progression7. The CDC25B-mediated dephosphorylation of Thr14 and Tyr15 residues in CDK1 activates this kinase and promotes the cell entry into mitosis. Thus, CDC25B can be considered as a mitotic inducer, because it participates in the cytoplasmic CDK1•cyclin B activation. The main role of CDC25C is to maintain the activated state of the CDK1•cyclin B complex in the nucleus, thus ensuring a full progression into mitosis4,8,. However, in adult tissues, the functions of three CDC25 paralogues can be compensatory among them9,10,.
Proteogenomic examination of esophageal squamous cell carcinoma (ESCC): new lines of inquiry
Published in Expert Review of Proteomics, 2020
Shobha Dagamajalu, Manavalan Vijayakumar, Rohan Shetty, D. A. B. Rex, Chinmaya Narayana Kotimoole, T. S. Keshava Prasad
Serum or other proximal body fluids have been explored for the discovery of candidate biomarkers as these are easily accessible samples with minimal invasion, when compared to tissue/tumor biopsies. Zhao et al. identified potential biomarkers including alpha-2-HS-glycoprotein (AHSG) and leucine-rich alpha-2-glycoprotein (LRG) for the early diagnosis of ESCC in serum [19]. Similarly, extracellular matrix 1 (ECM1), a protein also found in plasma, was discovered and suggested as a potential biomarker for the detection of primary ESCC and for the prediction of metastasis [20]. Nambu et al. have found the level of leucine-rich alpha-2-glycoprotein 1 (LRG1) to be low in the serum of ESCC patients, while responding to preoperative chemo-radiotherapy (PCRT). The study also suggested the combination of LRG1 with C-reactive protein (CRP) and soluble interleukin-6 receptor (sIL-6 R) can be used as candidate biomarkers for the prediction of response to PCRT [21]. Zhai et al. identified a 25.1 kDa protein in serum, which was found to be significantly increased during the development of the carcinogenesis of the esophagus and decreased after surgery and treatment [22]. Xu et al. have also shown that the SELDI-TOF-MS technique could be able to identify six protein peaks, which can be used as promising serum protein biomarkers for screening of ESCC [23]. Liu et al. have identified an autoantibody against CDC25B as a novel serum diagnostic marker for ESCC [24]. Autoantibody against HSP70 was also found to be significantly higher in the serum of ESCC patients compared to patients with other types of cancer [25]. Peroxiredoxin VI was identified in the ESCC cell line. An autoantibody against this antigen was also observed in the serum of ESCC patients which suggested its utility as a novel candidate as a serum biomarker for ESCC [26]. Overexpression of another three proteins such as serum amyloid A (SAA) and its isoform amyloid-related serum protein, and haptoglobin was observed in serum of ESCC patients after surgery compared to that of normal and pre-operation subjects. It indicated that these proteins might be associated with ESCC. However, the significance of these proteins in ESCC needs to be further characterized [27]. Ma et al. have carried out iTRAQ labeled quantitative proteomic approach using serum samples and observed downregulation of integrin-linked kinase (ILK) in chemo radiotherapy-sensitive group compared to chemo radiotherapy-resistant group in ESCC. Thus, it is suggested that ILK can be used for the prediction of the efficacy of chemo-radiotherapy in the treatment of ESCC [28].