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Roberts Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Inside the cell, four proteins (i.e., SMC1 [structural maintenance of chromosomes], SMC3, RAD21, and STAG1) interact to form a ring-like structure (cohesin ring or complex). With the help of NIPBL and Mau-2 proteins, this cohesin ring is loaded onto DNA during the G1 phase of the cell cycle. In S-phase, ESCO1/ESCO2 acetylate SMC3 (which may be deacetylated by HDAC8) and lock it in the cohesion ring that surrounds sister chromatids (forming so-called SCC); this ensures that only sister chromatids are paired together and that chromosomes are properly segregated later. During transition from prophase to prometaphase, cohesion between chromatid arms is cleaved through the anti-establishment pathway involving WAPL. During metaphase-to-anaphase transition, centromeric cohesin rings are removed by enzyme separase after proper bipolar attachment of all chromosomes to allow sister chromatid segregation to opposing spindle poles. The cofactors, PDS5, WAPL, and Sororin, are involved in association and/or dissociation with chromatin (Figure 47.1) [7–12].
Dopamine and Tumorigenesis in Reproductive Tissues
Published in Nira Ben-Jonathan, Dopamine, 2020
Subsequent studies revealed that PTTG is overexpressed in other tumors, including thyroid, breast and ovarian carcinomas. The PTTG protein, also known as human securin, induces cellular transformation, is involved in cell cycle regulation, and controls the segregation of sister chromatids during mitosis [10]. PTTG is an anaphase inhibitor that prevents premature chromosome separation through inhibition of separase activity; hence, its degradation is required to start anaphase. Through this important function, PTTG participates in several key cellular events such as mitosis, cell cycle progression, DNA repair, and apoptosis. Another putative oncogene, gsp (Gαs subunit) was overexpressed in ~40% of hormonally active pituitary adenomas [7]. Both cAMP [11] and cGMP [12] signaling cascades also appear to be involved in pituitary tumors.
Emerging strategies to target the dysfunctional cohesin complex in cancer
Published in Expert Opinion on Therapeutic Targets, 2019
Konstantinos Mintzas, Michael Heuser
Due to their important role in regulating and coordinating proper cohesin function, regulatory proteins such as the kinases and separase discussed above are important therapeutic targets. Inhibitors against these kinases can induce apoptosis in cells with normal cohesin function and may be useful for tumors with high RAD21 expression that has been linked to metastasis or tumors with high separase levels.
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].