Functionally Unequal Centrosomes Drive Spindle Orientation in Asymmetrically Dividing Drosophila Neural Stem Cells

Rebollo, Elena; Sampaio, Paula; Januschke, Jens; Llamazares, Salud; Varmark, Hanne; González, Cayetano

doi:10.1016/j.devcel.2007.01.021

Cited by 263 publications

(326 citation statements)

References 54 publications

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“…Mitotic spindles are perceived as a symmetric structure connecting the kinetochore of the duplicated chromatids with equal tension before separation (11,27). Conversely, asymmetric cell divisions were observed in neural and male germ stem cells in which the mother centrosome oriented toward the stem cell niche and the daughter centrosome migrated through chromosomes to the opposite side of the mother centrosome (36,37).…”

Section: Ibpr001 and Mln8237 Results In An Asymmetric Association Of Hmentioning

confidence: 99%

Aurora kinase inhibitors reveal mechanisms of HURP in nucleation of centrosomal and kinetochore microtubules

Wu¹,

Chen²,

Coumar

et al. 2013

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

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The overexpression of Aurora kinases in multiple tumors makes these kinases appealing targets for the development of anticancer therapies. This study identified two small molecules with a furanopyrimidine core, IBPR001 and IBPR002, that target Aurora kinases and induce a DFG conformation change at the ATP site of Aurora A. Our results demonstrate the high potency of the IBPR compounds in reducing tumorigenesis in a colorectal cancer xenograft model in athymic nude mice. Human hepatoma up-regulated protein (HURP) is a substrate of Aurora kinase A, which plays a crucial role in the stabilization of kinetochore fibers. This study used the IBPR compounds as well as MLN8237, a proven Aurora A inhibitor, as chemical probes to investigate the molecular role of HURP in mitotic spindle formation. These compounds effectively eliminated HURP phosphorylation, thereby revealing the coexistence and continuous cycling of HURP between unphosphorylated and phosphorylated forms that are associated, respectively, with microtubules emanating from centrosomes and kinetochores. Furthermore, these compounds demonstrate a spatial hierarchical preference for HURP in the attachment of microtubules extending from the mother to the daughter centrosome. The finding of inequality in the centrosomal microtubules revealed by these small molecules provides a versatile tool for the discovery of new cell-division molecules for the development of antitumor drugs.

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Section: Ibpr001 and Mln8237 Results In An Asymmetric Association Of Hmentioning

confidence: 99%

Aurora kinase inhibitors reveal mechanisms of HURP in nucleation of centrosomal and kinetochore microtubules

Wu¹,

Chen²,

Coumar

et al. 2013

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

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show abstract

“…Asymmetric cell divisions are well documented during the differentiation of stem cells (25), and in some cases the mother centrosome has been found to associate specifically with the stem cell during asymmetric divisions (26)(27)(28). Therefore, the asymmetric inheritance of pericentrosomal materials could potentially influence the outcome of stem cell differentiation decisions.…”

Section: Discussionmentioning

confidence: 99%

Asymmetric mitosis: Unequal segregation of proteins destined for degradation

Fuentealba

Eivers

Geissert

et al. 2008

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

156

140

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Mitotic cell division ensures that two daughter somatic cells inherit identical genetic material. Previous work has shown that signaling by the Smad1 transcription factor is terminated by polyubiquitinylation and proteasomal degradation after essential phosphorylations by MAPK and glycogen synthase kinase 3 (GSK3). Here, we show that, unexpectedly, proteins specifically targeted for proteasomal degradation are inherited preferentially by one mitotic daughter during somatic cell division. Experiments with dividing human embryonic stem cells and other mammalian cultured cell lines demonstrated that in many supposedly equal mitoses the segregation of proteins destined for degradation (Smad1 phosphorylated by MAPK and GSK3, phospho-␤-catenin, and total polyubiquitinylated proteins) was asymmetric. Transport of pSmad1 targeted for degradation to the centrosome required functional microtubules. In vivo, an antibody specific for Mad phosphorylated by MAPK showed that this antigen was associated preferentially with one of the two centrosomes in Drosophila embryos at cellular blastoderm stage. We propose that this remarkable cellular property may be explained by the asymmetric inheritance of peripheral centrosomal proteins when centrioles separate and migrate to opposite poles of the cell, so that one mitotic daughter remains pristine. We conclude that many mitotic divisions are unequal, unlike what was previously thought. Since the description of mitosis by Flemming in 1882, studies on somatic cell division have focused on the equal partition of cellular materials, in particular that of the chromosomes and mitotic apparatus, between cell daughters (1, 2). We now report that many mitotic divisions are unequal with respect to pericentrosomal proteins targeted for proteasomal degradation. The starting point for this investigation was provided by recent work showing that the duration of the Smad1 signal triggered by bone morphogenetic proteins (BMPs) is controlled by an elaborate protein degradation pathway (Fig. 1A). After activation via C-terminal phosphorylation by BMP receptor (BMPR), Smad1 is subjected to sequential phosphorylations by MAPK and glycogen synthase kinase 3 (GSK3) in its linker (middle) region. The MAPK and GSK3 phosphorylations are both required for the polyubiquitinylation and degradation of Smad1 (Fig. 1 A) (3, 4). We developed potent phospho-specific antibodies for positions Ser-214 (pSmad1 MAPK ) and Ser-210 (pSmad1 GSK3 ) that allow one to follow the intracellular location of Smad1 protein that has been specifically targeted for degradation (4).As is well known, centrosomes ensure that cells divide equally at mitosis and contain small centriole doublets surrounded by a matrix of proteins such as ␥-tubulin and pericentrin that serve as the microtubule-organizing center (MTOC) (2). In recent years, the realization has emerged that the centrosome also functions as the proteolytic center of the cell. The key to this discovery was the finding that cultured mammalian cells treated with proteasome inhibit...

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“…In particular, the Pins-Galphai-Mud complex is thought to anchor the aster of one of the spindle poles during mitosis (Bowman et al, 2006;Izumi et al, 2006;Siller et al, 2006). Combined live imaging of spindle assembly and centrosome function has shown that spindle orientation in larval NBs is determined, at least partially, from early interphase, much earlier than any of the known polarized markers can be seen at the apical cortex of the cell (Rebollo et al, 2007;Rusan and Peifer, 2007). Soon after cytokinesis, both centrosomes migrate to the nearest cortex, which roughly coincides with the region where apical markers were last localized.…”

Section: The Asymmetric Division Machinery Of Drosophila Nbsmentioning

confidence: 99%