Rapid microtubule-independent dynamics of Cdc20 at kinetochores and centrosomes in mammalian cells

Kallio, Marko J.; Beardmore, Victoria A.; Weinstein, Jasminder; Gorbsky, Gary J.

doi:10.1083/jcb.200201135

Cited by 126 publications

(126 citation statements)

References 20 publications

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“…Notably, many of the substrates, regulators or subunit proteins of the APC localize to the centrosome. These include cyclin B1 (57), CDC2/ CDK1 (70), CDC16/CDC27 (71), CDC20 (5,40,72), EMI1 (73), MAD1/MAD2 (40,51), BUB2 (47,48), Aurora-A kinase (21,74), and NEK2 (75). Among them CDC20, NEK2, cyclin B, and Aurora-A have been characterized as substrates of the CDH1-activated APC (17, 21, 76).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Localization of the Cell Cycle Regulator CDH1 and Its Regulation by Phosphorylation

Zhou

Ching

Chun

et al. 2003

Journal of Biological Chemistry

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The anaphase-promoting complex activated by CDC20 and CDH1 is a major ubiquitination system that controls the destruction of cell cycle regulators. Exactly how ubiquitination is regulated in time and space is incompletely understood. Here we report on the cell cycle-dependent localization of CDH1 and its regulation by phosphorylation. CDH1 localizes dynamically to the nucleus during interphase and to the centrosome during metaphase and anaphase. The nuclear accumulation of CDH1 correlates with a reduction in the steady-state amount of cyclin A, but not of cyclin E. A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus. On the other hand, abolition of the cyclin-binding ability of CDH1 has no influence on its nuclear localization. Taken together, our findings document the phosphorylation-dependent localization of CDH1 in vertebrate cells.The timely and orderly progression of eukaryotic cell division cycle is precisely controlled through ubiquitination-induced proteolysis. The anaphase-promoting complex (APC) 1 functions as a major ubiquitin ligase in the cell, and it governs anaphase onset, mitotic exit, and G 1 events (1-4). APC is a large complex of multiple subunits. It catalyzes the formation of polyubiquitin chains on cyclins and other cell cycle regulators and thereby targets them for degradation by proteosome. The components of APC are highly conserved in organisms ranging from yeast to humans. The rise and fall of APC activity is stringently regulated in a cell cycle-dependent manner. It plateaus at the transition from metaphase to anaphase, remains high throughout G 1 , and drops in S/G 2 until early mitosis (5). One important mechanism for the regulation of APC is through phosphorylation of its subunits (6 -9). In addition, CDC20 and CDH1 can act as activators and specificity factors of APC (10 -15).CDC20 and CDH1 are WD40 repeat proteins that associate transiently with and activate APC in a substrate-specific fashion. Many substrate proteins targeted by the CDC20-and CDH1-activated APC share a sequence motif known as destruction box (5, 16). Another motif termed the KEN box is recognized by CDH1-activated APC and has been found in substrates including CDC20, NEK2, HSL1, mitotic cyclins, and securin (17)(18)(19)(20). In addition, a distinct recognition domain called the A box has been shown to be required for CDH1-dependent ubiquitination and degradation of the Aurora-A kinase (21). Exactly how CDC20 and CDH1 activate APC remains to be fully understood. Existing evidence suggests that they mediate the temporal and spatial activation of APC throu...

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Section: Discussionmentioning

confidence: 99%

Nuclear Localization of the Cell Cycle Regulator CDH1 and Its Regulation by Phosphorylation

Zhou

Ching

Chun

et al. 2003

Journal of Biological Chemistry

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“…For fixation, we used 1% paraformaldehyde (Sigma) in PHEM buffer (details described in Kallio et al, 2002). The samples were analysed with a ZEISS Axioplan IIi microscope equipped with a Hamamatsu Orca II camera and Metamorph Imaging system (Universal Imaging Corp., Downingtown, PA, USA).…”

Section: Facs Analysis For Gfp-expressing Cellsmentioning

confidence: 99%

Tumor suppressor candidate TSSC5 is regulated by UbcH6 and a novel ubiquitin ligase RING105

Yamada

Gorbsky

2005

Oncogene

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The region of human chromosome 11p15.5 is linked with Beckwith-Wiedemann syndrome that is associated with susceptibility to Wilms' tumor, rhabdomyosarcoma and hepatoblastoma. TSSC5 (tumor-suppressing subchromosomal transferable fragment cDNA; also known as ORCTL2/IMPT1/BWR1A/SLC22A1L) is located in the region. The expression of TSSC5 and other genes in the region is regulated through paternal imprinting. Mutations and/or reduced expression of TSSC5 have been found in certain tumors. TSSC5 encodes an efflux transporter-like protein with 10 transmembrane domains, whose regulation may affect drug sensitivity, cellular metabolism and growth. Here, we present evidences indicating that RING105, a novel conserved RING-finger protein with a PA (protease-associated) domain and a PEST sequence, is a ubiquitin ligase for TSSC5 that can function in concert with the ubiquitin-conjugating enzyme UbcH6. The polyubiquitin target site on TSSC5 was mapped to a region in the 6th hydrophilic loop. Ectopic expression of RING105 in HeLa cells caused an accumulation of cells during G1 that was not observed with the expression of a form of RING105 in which a residue within the RING finger was mutated to inactivate its ligase activity. UbcH6-RING105 may define a novel ubiquitin-proteasome pathway that targets TSSC5 in mammalian cells.

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“…The specificity of the APC/C is governed by its interaction with the substrate-binding co-factors, Cdc20p/Slp1p and Cdh1p [reviewed in Vodermaier, 2001;Yu, 2002]. The Cdc20p and components of the APC/C also localize to kinetochores during SAC activation [Acquaviva et al, 2004;Kallio et al, 2002;Topper et al, 2002;Vigneron et al, 2004] but the questions of whether intact, functional APC/C is present at the kinetochore and whether this localized pool is specifically inhibited by SAC activation remain controversial.…”

Section: A Consensus Model For Spindle Checkpoint Functionmentioning

confidence: 99%

SAC‐ing mitotic errors: How the spindle assembly checkpoint (SAC) plays defense against chromosome mis‐segregation

Kadura

Sazer

2005

Cell Motil. Cytoskeleton

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Rapid microtubule-independent dynamics of Cdc20 at kinetochores and centrosomes in mammalian cells

Cited by 126 publications

References 20 publications

Nuclear Localization of the Cell Cycle Regulator CDH1 and Its Regulation by Phosphorylation

Nuclear Localization of the Cell Cycle Regulator CDH1 and Its Regulation by Phosphorylation

Tumor suppressor candidate TSSC5 is regulated by UbcH6 and a novel ubiquitin ligase RING105

SAC‐ing mitotic errors: How the spindle assembly checkpoint (SAC) plays defense against chromosome mis‐segregation

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