Mutations in the Essential Spindle Checkpoint Gene <i>bub1</i> Cause Chromosome Missegregation and Fail to Block Apoptosis in <i>Drosophila</i>

Basu, Joydeep; Bousbaa, Hassan; Logarinho, Elsa; Li, ZeXiao; Williams, Byron; Lopes, Carla S.; Sunkel, Cláudio E.; Goldberg, Michael L.

doi:10.1083/jcb.146.1.13

Cited by 179 publications

(108 citation statements)

References 68 publications

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“…Recent reports demonstrated that loss of APC caused chromosomal missegregation through ␤-catenin͞Wnt-independent mechanisms (36,37) and it is also possible that chromosomal missegregation may cause apoptosis (38,39). Therefore, we cannot exclude an possibility that apoptosis described here might be independent from dysregulation of ␤-catenin͞Wnt signaling.…”

Section: Resultsmentioning

confidence: 39%

Apoptosis in neural crest cells by functional loss of APC tumor suppressor gene

Hasegawa

Sato

Akazawa

et al. 2001

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

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Apc is a gene associated with familial adenomatous polyposis coli (FAP) and its inactivation is a critical step in colorectal tumor formation. The protein product, adenomatous polyposis coli (APC), acts to down-regulate intracellular levels of ␤-catenin, a key signal transducer in the Wnt signaling. Conditional targeting of Apc in the neural crest of mice caused massive apoptosis of cephalic and cardiac neural crest cells at about 11.5 days post coitum, resulting in craniofacial and cardiac anomalies at birth. Notably, the apoptotic cells localized in the regions where ␤-catenin had accumulated. In contrast to its role in colorectal epithelial cells, inactivation of APC leads to dysregulation of ␤-catenin͞Wnt signaling with resultant apoptosis in certain tissues including neural crest cells.T he Apc gene encoding a tumor suppressor protein, adenomatous polyposis coli (APC), is known to be responsible for familial adenomatous polyposis coli (FAP), an autosomaldominant inherited disorder characterized by multiple colorectal tumors (1, 2). Because Apc mutations are also frequently identified in sporadic colorectal tumors (3), the functional loss of APC is likely to be a key process in the colorectal tumorigenesis, especially during the early stages of tumor development. Indeed, conditional targeting of Apc in the colorectal epithelium initiated colorectal adenoma formation in mice (4).The biological function of APC is not fully understood, however it is thought to be a multifunctional protein and plays an important role in the regulation of growth, differentiation, and͞or migration of epithelial cells (5). Overexpression of APC can block cell cycle progression from G 0 ͞G 1 to S phase in NIH 3T3 cells (6). APC concentrates near the ends of microtubules that extend into actively migrating regions of epithelial cell membrane (7), and recently it was suggested that APC might regulate the actin cytoskeleton through Asef, a novel APCbinding protein (8). Moreover, the nuclear export function of APC has been reported by .Accumulating evidence has indicated that APC acts as a negative regulator of the Wnt signaling cascade through downregulation of ␤-catenin (10, 11). Functional loss of APC causes stabilization and accumulation of ␤-catenin (12), allowing it to form a complex with Tcf͞Lef transcription factors to activate Tcf target genes (13-15). Mutant mice lacking certain Wnt functions exhibited abnormal phenotypes involving embryonic induction, cell polarity, and cell fate determination in various tissues during development (16)(17)(18)(19)(20). In particular, injection of mRNA for ␤-catenin or that encoding a mutant form of Tcf-3 into zebrafish embryos affected the Wnt signaling and resulted in abnormal development of lateral and medial neural crest cells (21).To elucidate the function of APC in mammalian neural crest, in the present study we generated mutant mice harboring Apc disrupted specifically in the neural crest by using the Cre-loxP recombination system. We found that the mutant mice displayed severe craniofa...

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Section: Resultsmentioning

confidence: 39%

Apoptosis in neural crest cells by functional loss of APC tumor suppressor gene

Hasegawa

Sato

Akazawa

et al. 2001

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

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“…For example, Mad2 null mouse causes embryonic lethality and the Mad2 null embryos show high levels of chromosome mis-segregation and apoptosis (Dobles et al, 2000). Deletion of Bub1 in Drosophila is also embryonic lethal (Basu et al, 1999). It is unclear whether the spindle checkpoint is essential for early development of multicellular organisms or whether Mad2, Bub1, and other checkpoint genes have yet unidentified essential noncheckpoint functions.…”

Section: Defective Spindle Checkpoint and Aneuploidymentioning

confidence: 99%

The spindle checkpoint, aneuploidy, and cancer

2004

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“…These include rod (Karess and Glover 1989; Starr et al, 1998), the MAP kinases ppERK (Shapiro et al 1998; Zecevic et al 1998) and ppMEK (Shapiro et al 1998), and an APC activator protein fizzy (called cdc20/cdh1 in other organisms; Kallio et al 1998). Likewise, the protein kinase polo (Logarinho and Sunkel 1998) and a number of components of the highly conserved spindle assembly checkpoint, including Bub1 (Taylor and McKeon 1997; Taylor et al 1998; Basu et al 1999), Bub3 (Taylor et al 1998; Basu et al 1998; Martinez-Exposito et al 1999), Mad1 (Jin et al 1998; Chen et al 1998), and Mad2 (Waters et al 1998; Chen et al 1996, Chen et al 1998), are transiently kinetochore-bound.…”

Section: Introductionmentioning

confidence: 99%

CENP-meta, an Essential Kinetochore Kinesin Required for the Maintenance of Metaphase Chromosome Alignment in Drosophila

Yucel

Marszalek

McIntosh

et al. 2000

The Journal of Cell Biology

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CENP-meta has been identified as an essential, kinesin-like motor protein in Drosophila. The 257-kD CENP-meta protein is most similar to the vertebrate kinetochore-associated kinesin-like protein CENP-E, and like CENP-E, is shown to be a component of centromeric/kinetochore regions of Drosophila chromosomes. However, unlike CENP-E, which leaves the centromere/kinetochore region at the end of anaphase A, the CENP-meta protein remains associated with the centromeric/kinetochore region of the chromosome during all stages of the Drosophila cell cycle. P-element–mediated disruption of the CENP-meta gene leads to late larval/pupal stage lethality with incomplete chromosome alignment at metaphase. Complete removal of CENP-meta from the female germline leads to lethality in early embryos resulting from defects in metaphase chromosome alignment. Real-time imaging of these mutants with GFP-labeled chromosomes demonstrates that CENP-meta is required for the maintenance of chromosomes at the metaphase plate, demonstrating that the functions required to establish and maintain chromosome congression have distinguishable requirements.

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Mutations in the Essential Spindle Checkpoint Gene bub1 Cause Chromosome Missegregation and Fail to Block Apoptosis in Drosophila

Cited by 179 publications

References 68 publications

Apoptosis in neural crest cells by functional loss of APC tumor suppressor gene

Apoptosis in neural crest cells by functional loss of APC tumor suppressor gene

The spindle checkpoint, aneuploidy, and cancer

CENP-meta, an Essential Kinetochore Kinesin Required for the Maintenance of Metaphase Chromosome Alignment in Drosophila

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