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Aneuploidy in Human Oocytes and Preimplantation Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
The first genome-wide association study (GWAS) to identify common variants that affect aneuploidy in preimplantation embryos has been conducted. Using aneuploidy data from around 46,000 embryos (a mix of day 3 and day 5) from 4700 individuals, McCoy and colleagues found no association with putative maternal meiotic origin and maternal genotypes at the statistical significance threshold used. However, they found that a 600 Kb region (quantitative trait loci, QTL) of low recombination on chromosome 4 that was associated with multiple, complex aneuploidies of mitotic origin (they followed paternal chromosomes, since the meiotic error rate is very low in sperm). The QTL contained common variants of PLK4, a polo-like kinase that regulates centrosome numbers and whose dysregulation can lead to large-scale chromosome missegregation (122,123). Importantly, it was the maternal PLK4 variants that influenced mitotic chromosome segregation, consistent with the model that maternal factors drive the initial mitotic divisions in human preimplantation embryos (58,124,125). Although the QTL contains seven other gene variants, PLK4 is an attractive candidate since it regulates centriole duplication, a critical part of the centrosome cycle, and also mediates spindle formation during the initial cell divisions in mouse and bovine embryos (122,123). Thus, PLK4 variants may cause tripolar spindle formation that results in chaotic karyotypes (Figure 8.11). Importantly, tripolar spindles originating from normally fertilized human embryos have been observed (118).
Antitubulin Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The Polo-Like Kinases (PLKs) are a family of conserved serine/threonine kinases that are important regulators of the cell cycle through G2 and some phases of mitosis, including mitotic entry and exit, and cytokinesis. The “Polo” domain is named after the original protein encoded by the Polo gene of Drosophila melanogaster. These proteins are involved in the formation of, and modifications to, the mitotic spindle, and in the activation of CDK/Cyclin complexes during the M phase of the cell cycle. The PLKs are characterized by an amino terminal catalytic domain, and a carboxy terminal noncatalytic domain consisting of three blocks of conserved sequences known as Polo boxes which form one single functional domain. Mammalian PLKs include PLK1 (also known as STPK13), PLK2 (also known as SNK), PLK3 (also known as CNK, FNK, and PRK), PLK4 (also known as SAK or STK18), and PLK5. In particular, PLK1 acts in concert with Cyclin-dependent kinase 1 (Cyclin B1) and the Aurora kinases to orchestrate a wide range of critical cell-cycle events.
What value do cell cycle inhibitors have in the treatment of myelodysplastic syndrome?
Published in Expert Opinion on Pharmacotherapy, 2023
Maria Siddiqui, Gautam Borthakur
Oral hypomethylating agents, as monotherapy or combination regimens, have reinvigorated the therapeutic landscape. The ASCERTAIN trial reported a survival of 13 months in patients with biallelic TP53 MDS treated with oral decitabine-cedazuridine, a category with non-durable response to HMAs with a remarkably poor prognosis [29]. Similarly, combination treatment of oral decitabine-cedazuridine with magrolimab, an anti CD47 antibody is being studied in patients with high risk MDS based on phase III ENHANCE study (NCT04313881) [30]. Among other cell cycle agents, Polo-like kinase 4 (PLK4) inhibitor CFI-400945 has demonstrated early activity in high-risk AML. PLK4 over-expression is involved in centrosome amplification causing DNA instability. CFI-400945 is being studied as both monotherapy and in combination with HMAs [31]. Preclinical data show potential activity of azacitidine with cyclin-dependent kinase 9 (CDK-9) inhibitor, Alvocidib, in high-risk MDS with presence of ASXL1 mutations predicting response [32]. ATM-Rad3-related (ATR) inhibition sensitizes TP53 mutated MDS cells to decitabine providing a potential avenue for more durable responses in this group [33]. These novel agents offer the hope that MDS in the future could be treated entirely with an all oral regimen, which is an exciting prospect.
Identification of key genes, regulatory factors, and drug target genes of recurrent implantation failure (RIF)
Published in Gynecological Endocrinology, 2020
The decidualization refers to the proliferation and differentiation of ESCs into special secretory decidual cells, which are involved in the regulation of trophoblast invasion and uterine spiral artery remodeling [21,22]. The present results revealed that key DEGs were mainly involved in cell division and differentiation. Specifically, UBE2I, PLK4, XPO1, AURKB, and NUP107 were identified as the hub proteins based on the PPI network. UBE2I (Ubc9) is important for genome integrity, especially in mitosis and overall cell survival [23]. Zhu et al. demonstrated that UBE2I mRNA was up-regulated in tumor tissues of the ovary [24]. However, the correlation of UBE2I and endometrial need be further study. PLK4, an important member of the Polo-like serinethreonine kinase family, is essential for regulating centriole duplication [25]. The abnormal expressed PLK4 led to the tripolar mitosis and aneuploidy in human preimplantation embryo, which would result in RIF [26]. Besides, XPO1 was the target of different expressed miRNAs in endometriosis [27]. Moreover, AURKB promoted the attachment of the mitotic spindle to the centromere and expressed in a spatio-temporal pattern in mouse zygotes with the increased expression level in G1 phase and peaked at M phase [28]. NUP107 was reported to directly regulate the mitotic spindle assembly checkpoint protein MAD1 in mitotic functions [29]. Hub proteins mentioned above were involved in the RIF might affect the proliferation and differentiation of ESCs.
PLK4: a link between centriole biogenesis and cancer
Published in Expert Opinion on Therapeutic Targets, 2018
Radhika Radha Maniswami, Seema Prashanth, Archana Venkataramana Karanth, Sindhu Koushik, Hemalatha Govindaraj, Ramesh Mullangi, Sriram Rajagopal, Sooriya Kumar Jegatheesan
PLKs are the focus for cancer therapeutics due to their druggability and a central role in cellular growth pathways [17,18]. PLK4 is considered to be a potential therapeutic target as its levels dictates centriole duplication, a critical process for cell division. Usually PLK4 levels will be less in G1 phase, increases during S phase and reaches a maximum in G2/M phase. Hence, inhibition of PLK4 by mitosis-specific drugs may affect G1 or S phase tumor cells [174]. Also, PLK4 is expressed only in normal proliferating tissues and human tumors, but not in healthy nondividing cells which makes it an attractive and selective target for the development of cancer drugs [112,175,176].