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Myeloid/Lymphoid Neoplasms with Eosinophilia and Rearrangement
Published in Dongyou Liu, Tumors and Cancers, 2017
Occurring in the bone marrow and peripheral blood, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 are clonal diseases of hematopoietic stem cells, resulting from genetic and epigenetic alterations at PDGFRA (platelet-derived growth factor receptor alpha), PDGFRB (platelet-derived growth factor receptor beta), FGFR1 (fibroblast growth factor receptor 1 gene), or PCM1-JAK2 (human autoantigen pericentriolar material [PCM1] gene and Janus-activated kinase 2 [JAK2] fusion). These genetic changes affect the proliferation, differentiation, and self-renewal of eosinophils and lead to the release of granular contents [3,4].
Retinal dystrophy associated with a Kizuna (KIZ) mutation and a predominantly macular phenotype
Published in Ophthalmic Genetics, 2019
Yue Zhao, Razek Georges Coussa, Meghan J. M. DeBenedictis, Elias I. Traboulsi
Kizuna (KIZ) is a 673 amino acid protein encoded by 12kb on chromosome 20p11.23 and is involved in ciliary structural integrity. Studies in HeLA cell lines have demonstrated its role in maintaining centrosome stability during prometaphase (2). During mitosis, mature centrosomes, consisting of a pair of centrioles surrounded by pericentriolar material, form at each pole of the dividing cell. From the pericentriolar material, microtubules are successively enucleated to form spindle complexes that attach to the centrally aligned chromosomes and form scaffolding for chromatid separation (9,10). Oshimori et al. showed that phosphorylation of Kiz Thr-379 is required for centrosomal maturation and chromosomal movement (2). In the absence of Kiz, dissociation of pericentriolar material from the centrosome results in spindle fragmentation (1). In mice, Kizuna has been shown to be preferentially expressed in the retina, especially in the outer nuclear layer (1). It is hypothesized that the outer retina is predominantly affected by KIZ mutations. In the present case, KIZ c.226 C > T (p.Arg76*) is a nonsense mutation that results in a truncated non-functional protein and hence is pathogenic in a homozygous state.
Centrosome Abnormalities and Polyploidy in Murine Mammary Carcinomas with Different Degrees of Hormone Responsiveness
Published in Cancer Investigation, 2020
Melina Bilinski, Claudia Lanari, Victoria T. Fabris
Centrosomes are organelles formed by two centrioles surrounded by pericentriolar material (PCM) principally composed by γ-tubulin and pericentrin. Mammalian cells normally have one or two centrosomes depending on the phase of the cell cycle. Centrioles duplicate only once during the G1-S transition to form the poles of the mitotic spindle that nucleate the microtubules to which the chromosomes will attach during mitosis (reviewed in (9)).
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
Centrosomes are located in close proximity to the nucleus and function as the microtubule-organizing center in animal cells. Each centrosome comprises two barrel-shaped microtubule-based structures named centrioles [67]. A flexible linker connects the centrioles at their proximal ends [68,69]. A protein matrix referred to as pericentriolar material surrounds the proximal end of each centriole and is the locus of microtubule nucleation [67,70]. Centriole biogenesis occurs once per cell cycle and begins with the assembly of a procentriole structure orthogonally to each parental centriole during the G1 to S phase transition of the cell cycle [71,72]. In humans, CEP192 and CEP152 initiate centriole biogenesis by recruiting PLK4 to the proximal end of the parental centriole [73–76]. CDK11p58 is another mitotic protein kinase essential in recruitment of PLK4 to mitotic centrosomes [77]. An interaction between the PB3 domain of PLK4 and the coiled-coil domain (721-746aa) of STIL results in STIL phosphorylation and subsequent recruitment of SAS-6 [52,64,78,79]. PLK4-mediated phosphorylation at serine residues in STAN motifs of STIL or Ana2 was crucial for centriolar loading of SAS6. These residues are biologically significant throughout evolution as they are highly conserved from human STIL to Drosophila Ana2 [79,80]. Interaction of these proteins seeds the formation of a nine-fold symmetric cartwheel structure composed of SAS-6 homodimers [81,82]. Equally important is PLK4 mediated phosphorylation and subsequent inactivation of FBXW5 (SCF component) which stabilizes the cartwheel structure by preventing SAS-6 ubiquitination [83]. CPAP, CEP135 and γ-tubulin participate in the deposition of microtubules around the cartwheel promoting procentriole elongation [40]. CP110 localizes at the distal end of the elongating procentriole, gets phosphorylated by PLK4 at S98 position and is presumed to function as a cap in limiting microtubule extension [84,85]. CDK11p58 protein kinase is also involved in recruitment of PLK1 and gamma-tubulin during centrosome maturation [86]. Eventually, upon completion of procentriole elongation, distal lumen protein hPOC5 found in mature centrioles is incorporated into the procentriole structure [72,87]. Centriole duplication is tightly regulated by the close association of each procentriole with the parental centriole (referred to as engagement) during the entire process of duplication [71,88]. Disengagement by separase, a protease during late mitosis prevents reduplication of centriole during the same cell cycle [89,90]. PLK4 is an important regulator of centriole duplication. Excess PLK4 activity results in the formation of multiple centrioles, leading to rapid centrosome amplification as seen in tumor cells [91]. Low levels of PLK4 cause cell division failure as a consequence of abnormal spindle formation [43].