scholarly journals Hsp72 is targeted to the mitotic spindle by Nek6 to promote K-fiber assembly and mitotic progression

2015 ◽  
Vol 209 (3) ◽  
pp. 349-358 ◽  
Author(s):  
Laura O’Regan ◽  
Josephina Sampson ◽  
Mark W. Richards ◽  
Axel Knebel ◽  
Daniel Roth ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cancer Cell ◽  
Mitotic Spindle ◽  
Mitotic Progression ◽  
Nucleotide Binding Domain ◽  
Fiber Assembly ◽  
Spindle Poles ◽  
Chromosome Congression ◽  
Cancer Cell Survival ◽  
Spindle Microtubules

Hsp70 proteins represent a family of chaperones that regulate cellular homeostasis and are required for cancer cell survival. However, their function and regulation in mitosis remain unknown. In this paper, we show that the major inducible cytoplasmic Hsp70 isoform, Hsp72, is required for assembly of a robust bipolar spindle capable of efficient chromosome congression. Mechanistically, Hsp72 associates with the K-fiber–stabilizing proteins, ch-TOG and TACC3, and promotes their interaction with each other and recruitment to spindle microtubules (MTs). Targeting of Hsp72 to the mitotic spindle is dependent on phosphorylation at Thr-66 within its nucleotide-binding domain by the Nek6 kinase. Phosphorylated Hsp72 concentrates on spindle poles and sites of MT–kinetochore attachment. A phosphomimetic Hsp72 mutant rescued defects in K-fiber assembly, ch-TOG/TACC3 recruitment and mitotic progression that also resulted from Nek6 depletion. We therefore propose that Nek6 facilitates association of Hsp72 with the mitotic spindle, where it promotes stable K-fiber assembly through recruitment of the ch-TOG–TACC3 complex.

scholarly journals DDA3 recruits microtubule depolymerase Kif2a to spindle poles and controls spindle dynamics and mitotic chromosome movement

2008 ◽  
Vol 181 (2) ◽  
pp. 255-267 ◽  
Author(s):  
Chang-Young Jang ◽  
Jim Wong ◽  
Judith A. Coppinger ◽  
Akiko Seki ◽  
John R. Yates ◽  
...  
Keyword(s):  
Mitotic Spindle ◽  
Substantial Reduction ◽  
Genomic Analysis ◽  
Dependent Manner ◽  
Mitotic Progression ◽  
Spindle Poles ◽  
Functional Genomic Analysis ◽  
Chromosome Congression ◽  
Spindle Dynamics ◽  
Steady State Levels

Dynamic turnover of the spindle is a driving force for chromosome congression and segregation in mitosis. Through a functional genomic analysis, we identify DDA3 as a previously unknown regulator of spindle dynamics that is essential for mitotic progression. DDA3 depletion results in a high frequency of unaligned chromosomes, a substantial reduction in tension across sister kinetochores at metaphase, and a decrease in the velocity of chromosome segregation at anaphase. DDA3 associates with the mitotic spindle and controls microtubule (MT) dynamics. Mechanistically, DDA3 interacts with the MT depolymerase Kif2a in an MT-dependent manner and recruits Kif2a to the mitotic spindle and spindle poles. Depletion of DDA3 increases the steady-state levels of spindle MTs by reducing the turnover rate of the mitotic spindle and by increasing the rate of MT polymerization, which phenocopies the effects of partial knockdown of Kif2a. Thus, DDA3 represents a new class of MT-destabilizing protein that controls spindle dynamics and mitotic progression by regulating MT depolymerases.

scholarly journals The myosin regulatory light chain Myl5 localizes to mitotic spindle poles and is required for proper cell division

2020 ◽  
Author(s):  
Ivan Ramirez ◽  
Ankur A. Gholkar ◽  
Erick F. Velasquez ◽  
Xiao Guo ◽  
Jorge Z. Torres
Keyword(s):  
Cell Division ◽  
Molecular Motors ◽  
Mitotic Spindle ◽  
Regulatory Light Chains ◽  
Cellular Processes ◽  
Spindle Poles ◽  
Chromosome Congression ◽  
Mitotic Spindle Assembly ◽  
Spindle Microtubules ◽  
Early Mitosis

ABSTRACTMyosins are ATP-dependent actin-based molecular motors critical for diverse cellular processes like intracellular trafficking, cell motility and cell invasion. During cell division, myosin MYO10 is important for proper mitotic spindle assembly, the anchoring of the spindle to the cortex, and positioning of the spindle to the cell mid-plane, while myosin MYO2 functions in actomyosin ring contraction to promote cytokinesis. However, myosins are regulated by myosin regulatory light chains (RLCs), and whether RLCs are important for cell division has remained unexplored. Here, we have determined that the previously uncharacterized myosin RLC Myl5 associates with the mitotic spindle and is required for cell division. Myl5 localized to the mitotic spindle poles and spindle microtubules during early mitosis, an area overlapping with MYO10 localization. Depletion of Myl5 led to defects in chromosome congression and to a slower progression through mitosis. We propose that Myl5 is a novel myosin RLC that is important for cell division.

Co-targeting EGFR and Autophagy Impairs Ovarian Cancer Cell Survival during Detachment from the ECM

2015 ◽  
Vol 15 (3) ◽  
pp. 215-226 ◽  
Author(s):  
Zongyuan Yang ◽  
Yi Liu ◽  
Xiao Wei ◽  
Xiaoshui Zhou ◽  
Cheng Gong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Survival ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Survival

AMPA Receptor Antagonist CFM-2 Decreases Survivin Expression in Cancer Cells

2018 ◽  
Vol 18 (4) ◽  
pp. 591-596 ◽  
Author(s):  
Domingo Sanchez Ruiz ◽  
Hella Luksch ◽  
Marco Sifringer ◽  
Achim Temme ◽  
Christian Staufner ◽  
...  
Keyword(s):  
Cell Survival ◽  
Receptor Antagonist ◽  
Cancer Cells ◽  
Glutamate Receptors ◽  
Cancer Cell ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Survivin Expression ◽  
Ampa Receptor Antagonist ◽  
Cancer Cell Survival

Background: Glutamate receptors are widely expressed in different types of cancer cells. α-Amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors are ionotropic glutamate receptors which are coupled to intracellular signaling pathways that influence cancer cell survival, proliferation, and migration. Blockade of AMPA receptors by pharmacologic compounds may potentially constitute an effective tool in anticancer treatment strategies. Method: Here we investigated the impact of the AMPA receptor antagonist CFM-2 on the expression of the protein survivin, which is known to promote cancer cell survival and proliferation. We show that CFM-2 inhibits survivin expression at mRNA and protein levels and decreases the viability of cancer cells. Using a stably transfected cell line which overexpresses survivin, we demonstrate that over-expression of survivin enhances cancer cell viability and attenuates CFM-2–mediated inhibition of cancer cell growth. Result: These findings point towards suppression of survivin expression as a new mechanism contributing to anticancer effects of AMPA antagonists.

scholarly journals The ERG-Regulated LINC00920 Promotes Prostate Cancer Cell Survival via the 14-3-3ε–FOXO Pathway

2020 ◽  
Vol 18 (10) ◽  
pp. 1545-1559
Author(s):  
Arlou Kristina Angeles ◽  
Doreen Heckmann ◽  
Niclas Flosdorf ◽  
Stefan Duensing ◽  
Holger Sültmann
Keyword(s):  
Prostate Cancer ◽  
Cell Survival ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Cancer Cell Survival

scholarly journals LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

Oncogenesis ◽  
2021 ◽  
Vol 10 (2) ◽  
Author(s):  
Yu Geon Lee ◽  
Hui Won Kim ◽  
Yeji Nam ◽  
Kyeong Jin Shin ◽  
Yu Jin Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Cell Survival ◽  
Cancer Cell ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Tca Cycle ◽  
Mitochondrial Matrix ◽  
Mitochondrial Functions ◽  
Cancer Cell Survival

AbstractMitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer.

Fr154 SMOKING INDUCES WEE1 EXPRESSION PROMOTING CANCER CELL SURVIVAL IN ESOPHAGEAL ADENOCARCINOMA

2021 ◽  
Vol 160 (6) ◽  
pp. S-240
Author(s):  
Zheng Chen ◽  
Heng Lu ◽  
Dunfa Peng ◽  
Wael El-Rifai
Keyword(s):  
Cell Survival ◽  
Esophageal Adenocarcinoma ◽  
Cancer Cell ◽  
Cancer Cell Survival
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