Timely anaphase onset requires a novel spindle and kinetochore complex comprising Ska1 and Ska2

Hanisch, Anja; Silljé, Herman H W; Nigg, Erich A.

doi:10.1038/sj.emboj.7601426

Cited by 228 publications

(341 citation statements)

References 34 publications

(54 reference statements)

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“…S5B, S7B, and S8B). Although GR is known to interact with the kinetochore protein Ska2 (23,24), the distribution of P S211GR overlying the condensed chromosomes and kinetochores was not consistently lost with both GR siRNAs (SI Appendix, Figs. S8B and S9), suggesting that this immunoreactivity may be due to cross-reaction with another phosphorylated protein.…”

Section: Significancementioning

confidence: 99%

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

Matthews

Berry

Morgan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily, which controls programs regulating cell proliferation, differentiation, and apoptosis. We have identified an unexpected role for GR in mitosis. We discovered that specifically modified GR species accumulate at the mitotic spindle during mitosis in a distribution that overlaps with Aurora kinases. We found that Aurora A was required to mediate mitosis-driven GR phosphorylation, but not recruitment of GR to the spindle. GR was necessary for mitotic progression, with increased time to complete mitosis, frequency of mitotic aberrations, and death in mitosis observed following GR knockdown. Complementation studies revealed an essential role for the GR ligand-binding domain, but no clear requirement for ligand binding in regulating chromosome segregation. The GR N-terminal domain, and specifically phosphosites S203 and S211, were not required. Reduced GR expression results in a cell cycle phenotype, with isolated cells from mouse and human subjects showing changes in chromosome content over prolonged passage. Furthermore, GR haploinsufficient mice have an increased incidence of tumor formation, and, strikingly, these tumors are further depleted for GR, implying additional GR loss as a consequence of cell transformation. We identified reduced GR expression in a panel of human liver, lung, prostate, colon, and breast cancers. We therefore reveal an unexpected role for the GR in promoting accurate chromosome segregation during mitosis, which is causally linked to tumorigenesis, making GR an authentic tumor suppressor gene.glucocorticoid receptor | mitosis | aneuploidy | DNA damage | cancer G lucocorticoids (Gcs) act through the glucocorticoid receptor (GR), a member of the nuclear hormone receptor superfamily, and a ligand-activated transcription factor (1-4). The GR is ubiquitously expressed and regulates energy metabolism, immunity, and cell fate decisions. The quiescent GR resides in the cytoplasm in a complex with heat shock proteins and immunophilins, attached to the microtubule architecture of the cell in a heat shock protein 90-dependent manner (5). Ligand binding drives GR transformation, involving N-terminal phosphorylation on S203 and S211 and rapid translocation to the nucleus requiring attachment to dynein by heat shock protein 90, immunophilins, and dynamitin (6). Once in the nucleus, GR binds directly to DNA to regulate transcription, or tethers to other DNA-bound transcription factors, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP1), to regulate their function (7-10).In mitosis, GR is phosphorylated on both S203 and S211, but in a ligand-independent manner (11), and more comprehensive phosphoproteomic analyses identify the presence of multiple N-terminal GR phosphoforms in purified mitotic spindle fractions (12). Although altered GR function in mitosis has been shown (11, 13, 14), the kinases responsible and cellular consequences have not been defined. The role of G...

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Section: Significancementioning

confidence: 99%

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

Matthews

Berry

Morgan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…How can this be reconciled? One possibility is that functional counterparts of the Dam1 complex exist in metazoa, albeit with little homology in amino acid sequences; Ska1/2, Cep57, and Bod1 are such candidates (Hanisch et al 2006;Emanuele and Stukenberg 2007;Porter and Swedlow 2007), although their functional similarity to the Dam1 complex must be studied further. Alternatively, the role of the Dam1 complex may be more important in organisms such as budding yeast, in which a single kinetochore attaches to a single microtubule in metaphase (Winey et al 1995).…”

Section: Interface Of Kinetochore Microtubule Interaction: the Ndc80 mentioning

confidence: 99%

Bi-orienting chromosomes: acrobatics on the mitotic spindle

Tanaka

2008

Chromosoma

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To maintain their genetic integrity, eukaryotic cells must segregate their chromosomes properly to opposite poles during mitosis. This process mainly depends on the forces generated by microtubules that attach to kinetochores. During prometaphase, kinetochores initially interact with a single microtubule that extends from a spindle pole and then move towards a spindle pole. Subsequently, microtubules that extend from the other spindle pole also interact with kinetochores and, eventually, each sister kinetochore attaches to microtubules that extend from opposite poles (sister kinetochore bi-orientation). If sister kinetochores interact with microtubules in wrong orientation, this must be corrected before the onset of anaphase. Here, I discuss the processes leading to biorientation and the mechanisms ensuring this pivotal state that is required for proper chromosome segregation.

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“…This difference has been postulated to reflect the more stringent requirement for maintaining connection with the depolymerizing microtubule when a single point of attachment is present; thus, under these circumstances, the ring may provide necessary stability (Burrack et al, 2011;Thakur & Sanyal, 2011). Outside of the yeasts, sequence-based homologues of the Dam1 complex proteins are not identifiable, though a variety of evidence suggests that the functional homologue in metazoans may be the Ska complex (Gaitanos et al, 2009;Guimaraes & Deluca, 2009;Hanisch, Sillje, & Nigg, 2006;Jeyaprakash et al, 2012;Welburn et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Divalent Cations Affect the Stability and Structure of Dad2p, a Subunit of the Candida Albicans Kinetochore Dam1 Complex

Waldo¹,

Dolma²,

Rouse³

2016

JMBR

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The heterodecameric Dam1 complex is involved in establishing and maintaining the connection between the kinetochore and the mitotic spindle during mitosis. Biochemical studies of the reconstituted complex have shed light upon how it interacts with microtubules. However, little information about the biochemical properties of the isolated subunits has been available. This report examines the stability and structure of Dad2p, one of the Dam1 complex subunits isolated from Candida albicans. By employing differential scanning fluorimetry, protease protection and hydrodynamic analyses, we show that Dad2p is specifically responsive to the presence of divalent cations. This observation may be important for understanding the dynamic structure and regulation of the Dam1 complex in fungal cells.

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Timely anaphase onset requires a novel spindle and kinetochore complex comprising Ska1 and Ska2

Cited by 228 publications

References 34 publications

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

Bi-orienting chromosomes: acrobatics on the mitotic spindle

Divalent Cations Affect the Stability and Structure of Dad2p, a Subunit of the Candida Albicans Kinetochore Dam1 Complex

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