Expression of the kinetochore protein Hec1 during the cell cycle in normal and cancer cells and its regulation by the pRb pathway

Ferretti, Carlo; Totta, Pierangela; Fiore, Mario; Mattiuzzo, Marta; Schillaci, Tiziano; Ricordy, R.; Leonardo, Aldo Di; Degrassi, Francesca

doi:10.4161/cc.9.20.13457

Cited by 27 publications

(28 citation statements)

References 38 publications

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“…Previous work has shown that Nek2 may participate in chromosome condensation through its interactions with Hec1 (30), and Nek2-dependent phosphorylaton of Hec1 is essential for kinetochore attachments to microtubules during mitosis (37). Hec1 is functionally linked to the pRb pathway because disruption of pRb activity leads to Hec1 overexpression, inducing defects in chromosome segregation and mitosis (38). Collectively, these data suggest that Nek2 may be involved in regulating both the histone H3 and pRb pathways.…”

Section: Discussionmentioning

confidence: 65%

Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells

et al. 2013

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Breast cancer is the most common solid tumor and the second most common cause of death in women. Despite a large body of literature and progress in breast cancer research, many molecular aspects of this complex disease are still poorly understood, hindering the design of specific and effective therapeutic strategies. To identify molecules important in breast cancer progression and metastasis, we tested the in vivo effects of inhibiting the functions of various kinases and genes involved in the regulation/modulation of the cytoskeleton by downregulating them in mouse PyMT mammary tumor cells and human breast cancer cell lines. These kinases and cytoskeletal regulators were selected based on their prognostic values for breast cancer patient survival. PyMT tumor cells in which a selected gene was stably knocked down were injected into the tail veins of mice and the formation of tumors in the lungs was monitored. One of several genes found to be important for tumor growth in lungs was Nek2, a cell cycle-related protein kinase. Furthermore, Nek2 was also important for tumor growth in the mammary fat pad.In various human breast cancer cell lines, Nek2 knockdown induced aneuploidy and cell cycle arrest that led to cell death. Significantly, the breast cancer cell line most sensitive to Nek2 depletion was of the triple negative breast cancer subtype. Our data indicate that Nek2 plays a pivotal role in breast cancer growth at primary and secondary sites, and thus may be an attractive and novel therapeutic target for this disease.

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Section: Discussionmentioning

confidence: 65%

Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells

et al. 2013

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“…Importantly, altered expression of any of the spindle-associated proteins may contribute to unbalanced chromosome segregation during mitosis. Indeed, increased expression of NDC80 and SMC2 has been observed in cancer cells and an increased requirement for NDC80 at kinetochores of cancer cells has been postulated (Ferretti et al, 2010; Dávalos et al, 2012). Interestingly, some SRSF1 translational targets, including NDC80 and centrosomal proteins, have been previously identified in an siRNA screen looking for proteins involved in centrosome clustering in cancer cells (Leber et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

The translational landscape of the splicing factor SRSF1 and its role in mitosis

Maslon

Heras

Bellora

et al. 2014

eLife

113

126

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The shuttling serine/arginine rich (SR) protein SRSF1 (previously known as SF2/ASF) is a splicing regulator that also activates translation in the cytoplasm. In order to dissect the gene network that is translationally regulated by SRSF1, we performed a high-throughput deep sequencing analysis of polysomal fractions in cells overexpressing SRSF1. We identified approximately 1500 mRNAs that are translational targets of SRSF1. These include mRNAs encoding proteins involved in cell cycle regulation, such as spindle, kinetochore, and M phase proteins, which are essential for accurate chromosome segregation. Indeed, we show that translational activity of SRSF1 is required for normal mitotic progression. Furthermore, we found that mRNAs that display alternative splicing changes upon SRSF1 overexpression are also its translational targets, strongly suggesting that SRSF1 couples pre-mRNA splicing and translation. These data provide insights on the complex role of SRSF1 in the control of gene expression at multiple levels and its implications in cancer.DOI: http://dx.doi.org/10.7554/eLife.02028.001

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“…Hec1 is of particular interest as disruption of Rb function has been shown to lead to mitotic defects through Hec1 overexpression in other cell lines. 30 While some variability in Hec1 staining intensity between mitotic cells was observed, we did not observe qualitative differences in Hec1 staining between the Rb-positive and Rbdeficient cells (Fig. 4D).…”

Section: Ilk Inhibition Increases Multinucleation In Rb Positive and mentioning

confidence: 52%

Integrin-linked kinase regulates senescence in an Rb-dependent manner in cancer cell lines

et al. 2015

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Anti-integrin-linked kinase (ILK) therapies result in aberrant mitosis including altered mitotic spindle organization, centrosome declustering and mitotic arrest. In contrast to cells that expressed the retinoblastoma tumor suppressor protein Rb, we have shown that in retinoblastoma cell lines that do not express Rb, anti-ILK therapies induced aberrant mitosis that led to the accumulation of temporarily viable multinucleated cells. The present work was undertaken to: 1) determine the ultimate fate of cells that had survived anti-ILK therapies and 2) determine whether or not Rb expression altered the outcome of these cells. Our data indicate that ILK, a chemotherapy drug target is expressed in both welldifferentiated, Rb-negative and relatively undifferentiated, Rb-positive retinoblastoma tissue. We show that small molecule targeting of ILK in Rb-positive and Rb-deficient cancer cells results in increased centrosomal declustering, aberrant mitotic spindle formation and multinucleation. However, anti-ILK therapies in vitro have different outcomes in retinoblastoma and glioblastoma cell lines that depend on Rb expression. TUNEL labeling and propidium iodide FACS analysis indicate that Rb-positive cells exposed to anti-ILK therapies are more susceptible to apoptosis and senescence than their Rb-deficient counterparts wherein aberrant mitosis induced by anti-ILK therapies exhibit mitotic arrest instead. These studies are the first to show a role for ILK in chemotherapy-induced senescence in Rb-positive cancer lines. Taken together these results indicate that the oncosuppressive outcomes for anti-ILK therapies in vitro, depend on the expression of the tumor suppressor Rb, a known G 1 checkpoint and senescence regulator.

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Expression of the kinetochore protein Hec1 during the cell cycle in normal and cancer cells and its regulation by the pRb pathway

Cited by 27 publications

References 38 publications

Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells

Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells

The translational landscape of the splicing factor SRSF1 and its role in mitosis

Integrin-linked kinase regulates senescence in an Rb-dependent manner in cancer cell lines

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