Spatial regulation of Aurora A activity during mitotic spindle assembly requires RHAMM to correctly localize TPX2

Chen, Helen; Mohan, Pooja; Jiang, Jihong; Nemirovsky, Oksana; He, Daniel; Fleisch, Markus; Niederacher, Dieter; Pilarski, Linda M.; Lim, C. J.; Maxwell, Christopher A.

doi:10.4161/cc.29270

Cited by 45 publications

(73 citation statements)

References 44 publications

(79 reference statements)

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“…HMMR interacts with dynein adaptor proteins and through these complexes controls spindle position [13], which likely complements the actions of PLK1 and Ran-GTP [10]. Moreover, HMMR promotes PLK1 activity at kinetochores [20], which has been shown to strip LGN from the cortex when brought proximal on misaligned chromosomes [12]. Thus, it is reasonable to predict that PLK1 activity is augmented in BRCA1-depleted mitotic cells both through the stabilization of HMMR [20] and the removal of direct suppression of the kinase by BRCA1 [19].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, HMMR promotes PLK1 activity at kinetochores [20], which has been shown to strip LGN from the cortex when brought proximal on misaligned chromosomes [12]. Thus, it is reasonable to predict that PLK1 activity is augmented in BRCA1-depleted mitotic cells both through the stabilization of HMMR [20] and the removal of direct suppression of the kinase by BRCA1 [19]. Thus, loss of cortical NUMA-dynein complexes and a cell-autonomous deficit in spindle positioning observed following BRCA1 suppression is mechanistically explained by the stabilization of HMMR and augmented PLK1 activity predicted to occur along the spindle.…”

Section: Discussionmentioning

confidence: 99%

“…Mechanistically, BRCA1 reduces PLK1 activity [19] and forms mutually exclusive complexes with NUMA or HMMR to regulate Ran-dependent microtubule assembly [17] and promote the degradation of HMMR [16]. HMMR is also an upstream regulator for aurora kinase A [20, 21], which is known to influence symmetric division in mammary epithelial cells [22]. These tumor-suppressive actions may be specific for BRCA1, as polymorphisms in HMMR modify breast cancer risk associated with mutations in BRCA1 but not BRCA2 [23].…”

Section: Introductionmentioning

confidence: 99%

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BRCA1 controls the cell division axis and governs ploidy and phenotype in human mammary cells

Kannan

Nemirovsky

et al. 2017

Oncotarget

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BRCA1 deficiency may perturb the differentiation hierarchy present in the normal mammary gland and is associated with the genesis of breast cancers that are genomically unstable and typically display a basal-like transcriptome. Oriented cell division is a mechanism known to regulate cell fates and to restrict tumor formation. We now show that the cell division axis is altered following shRNA-mediated BRCA1 depletion in immortalized but non-tumorigenic, or freshly isolated normal human mammary cells with graded consequences in progeny cells that include aneuploidy, perturbation of cell polarity in spheroid cultures, and a selective loss of cells with luminal features. BRCA1 depletion stabilizes HMMR abundance and disrupts cortical asymmetry of NUMA-dynein complexes in dividing cells such that polarity cues provided by cell-matrix adhesions were not able to orient division. We also show that immortalized mammary cells carrying a mutant BRCA1 allele (BRCA1 185delAG/+) reproduce many of these effects but in this model, oriented divisions were maintained through cues provided by CDH1+ cell-cell junctions. These findings reveal a previously unknown effect of BRCA1 suppression on mechanisms that regulate the cell division axis in proliferating, non-transformed human mammary epithelial cells and consequent downstream effects on the mitotic integrity and phenotype control of their progeny.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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BRCA1 controls the cell division axis and governs ploidy and phenotype in human mammary cells

Kannan

Nemirovsky

et al. 2017

Oncotarget

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“…RHAMM acts as a cell-surface receptor for hyaluronan (HA) and as intracellular stabilizer of the mitotic spindle [12]. Its functional role is thought to be the response to pathological process and was shown to be increased in various tumors [13].…”

Section: Introductionmentioning

confidence: 99%

RHAMM splice variants confer radiosensitivity in human breast cancer cell lines

et al. 2016

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Biomarkers for prognosis in radiotherapy-treated breast cancer patients are urgently needed and important to stratify patients for adjuvant therapies. Recently, a role of the receptor of hyaluronan-mediated motility (RHAMM) has been suggested for tumor progression. Our aim was (i) to investigate the prognostic value of RHAMM in breast cancer and (ii) to unravel its potential function in the radiosusceptibility of breast cancer cells. We demonstrate that RHAMM mRNA expression in breast cancer biopsies is inversely correlated with tumor grade and overall survival. Radiosusceptibility in vitro was evaluated by sub-G1 analysis (apoptosis) and determination of the proliferation rate. The potential role of RHAMM was addressed by short interfering RNAs against RHAMM and its splice variants. High expression of RHAMMv1/v2 in p53 wild type cells (MCF-7) induced cellular apoptosis in response to ionizing radiation. In comparison, in p53 mutated cells (MDA-MB-231) RHAMMv1/v2 was expressed sparsely resulting in resistance towards irradiation induced apoptosis. Proliferation capacity was not altered by ionizing radiation in both cell lines. Importantly, pharmacological inhibition of the major ligand of RHAMM, hyaluronan, sensitized both cell lines towards radiation induced cell death. Based on the present data, we conclude that the detection of RHAMM splice variants in correlation with the p53 mutation status could help to predict the susceptibility of breast cancer cells to radiotherapy. Additionally, our studies raise the possibility that the response to radiotherapy in selected cohorts may be improved by pharmaceutical strategies against RHAMM and its ligand hyaluronan.

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“…Beyond CK1a, the phosphorylation-mediated control of spindle positioning has been attributed to several other protein kinases. Of note, the activity of CDKs, PLKs and Aurora kinases have all been shown to critically regulate spindle positioning [15,[43][44][45][46][47][48][49][50]. Both their recruitment to the mitotic spindle and activities are tightly regulated [44,46,51,52].…”

Section: Discussionmentioning

confidence: 99%

FAM 83D directs protein kinase CK 1α to the mitotic spindle for proper spindle positioning

Fulcher

Mei

et al. 2019

EMBO Reports

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The concerted action of many protein kinases helps orchestrate the error‐free progression through mitosis of mammalian cells. The roles and regulation of some prominent mitotic kinases, such as cyclin‐dependent kinases, are well established. However, these and other known mitotic kinases alone cannot account for the extent of protein phosphorylation that has been reported during mammalian mitosis. Here we demonstrate that CK1α, of the casein kinase 1 family of protein kinases, localises to the spindle and is required for proper spindle positioning and timely cell division. CK1α is recruited to the spindle by FAM83D, and cells devoid of FAM83D , or those harbouring CK1α‐binding‐deficient FAM83D F283A/F283A knockin mutations, display pronounced spindle positioning defects, and a prolonged mitosis. Restoring FAM83D at the endogenous locus in FAM83D − / − cells, or artificially delivering CK1α to the spindle in FAM83D F283A/F283A cells, rescues these defects. These findings implicate CK1α as new mitotic kinase that orchestrates the kinetics and orientation of cell division.

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Spatial regulation of Aurora A activity during mitotic spindle assembly requires RHAMM to correctly localize TPX2

Cited by 45 publications

References 44 publications

BRCA1 controls the cell division axis and governs ploidy and phenotype in human mammary cells

BRCA1 controls the cell division axis and governs ploidy and phenotype in human mammary cells

RHAMM splice variants confer radiosensitivity in human breast cancer cell lines

FAM 83D directs protein kinase CK 1α to the mitotic spindle for proper spindle positioning

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