Regulation of Cyclin A-Cdk2 by SCF Component Skp1 and F-Box Protein Skp2

Yam, Chit Hong; Ng, Raymond W. M.; Siu, Wai Yi; Lau, Anita Wan Sze; Poon, Randy Y. C.

doi:10.1128/mcb.19.1.635

Cited by 72 publications

(57 citation statements)

References 37 publications

(49 reference statements)

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“…Moreover, histopathological and cellular abnormalities seen in Skp2 −/− mice, including polyploidy, enlargement of nuclei and endoreduplication, are abolished in Skp2/p27 double knockout mice ( [38] and Nakayama, personal communication), suggesting that p27 is a primary target of Skp2. Other substrates have been proposed for Skp2 including cyclin D1, B-Myb, and E2F-1 [37,39,40]; however, these potential substrates were not shown to accumulate in cells from Skp2 −/− mice, suggesting that either they are not bona fide Skp2 substrates or there is redundancy allowing for their ubiquitination in the absence of Skp2. Cks1 −/− mice have also been generated and are smaller than wild-type littermates.…”

Section: P27 As a Tumor Suppressor In Mouse Modelsmentioning

confidence: 94%

Deregulated degradation of the cdk inhibitor p27 and malignant transformation

Bloom

Pagano

2003

Seminars in Cancer Biology

335

317

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Section: P27 As a Tumor Suppressor In Mouse Modelsmentioning

confidence: 94%

Deregulated degradation of the cdk inhibitor p27 and malignant transformation

Bloom

Pagano

2003

Seminars in Cancer Biology

335

317

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“…and EcoRI, and ligated into pUHD-P1 (Yam et al, 1999a) or pUHD-P1/3C (Fung et al, 2005). FLAG-cyclin B1 in pUHD-P1 was amplified by PCR with vector forward primer and 5 0 -GATCAGCTCCATTTTCTGCATC-3 0 ; the PCR product was cut with NcoI, and ligated into pUHD-P1 cut with NcoI and BamHI (blunt with Klenow fragment) to produce FLAGcyclin B1(CD160) in pUHD-P1.…”

Section: Dna Constructsmentioning

confidence: 99%

Generation of an indestructible cyclin B1 by caspase-6-dependent cleavage during mitotic catastrophe

2008

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Overriding the G 2 DNA damage checkpoint permits precocious entry into mitosis that ultimately leads to mitotic catastrophe. Mitotic catastrophe is manifested by an unscheduled activation of CDK1, caspase activation and apoptotic cell death. We found that although cyclin B1 was required for mitotic catastrophe, it was cleaved into a B35 kDa protein by a caspase-dependent mechanism during the process. Cyclin B1 cleavage occurred after Asp123 in the motif ILVD 123 k, and mutation of this motif attenuated the cleavage. Cleavage was abolished by a pan-caspase inhibitor as well as by specific inhibitors for the effector caspase-6 and the initiator caspase-8. Cleavage created a truncated cyclin B1 lacking part of the NH 2 -terminal regulatory domain that included the destruction box sequence. Although cleavage of cyclin B1 itself was not absolutely required for mitotic catastrophe, expression of the truncated product enhanced cell death. In support of this, ectopic expression of this truncated cyclin B1 was not only sufficient to induce mitotic block and apoptosis but also enhanced mitotic catastrophe induced by ionizing radiation and caffeine. These data underscore a possible linkage between mitotic and apoptotic functions by caspase-dependent processing of mitotic activators.

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“…FLAG-cyclin A-cyclin F(N⌬565) (cyclin A fused to the PEST region of cyclin F) was created by putting the NcoI-cut fragment of cyclin A generated from PCR into FLAG-cyclin F(N⌬565) in pUHD-P1. FLAG-SKP2 for mammalian expression and cyclin A and cyclin A(N⌬71) (⌬D-box) for reticulocyte lysate expression were as described previously (31). Human ubiquitin cDNA was a gift from Dr. Tim Hunt (Cancer Research UK).…”

Section: Methodsmentioning

confidence: 99%

Cyclin F Is Degraded during G2-M by Mechanisms Fundamentally Different from Other Cyclins

Fung

Siu

Yam³

et al. 2002

Journal of Biological Chemistry

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Cyclin F, a cyclin that can form SCF complexes and bind to cyclin B, oscillates in the cell cycle with a pattern similar to cyclin A and cyclin B. Ectopic expression of cyclin F arrests the cell cycle in G 2 /M. How the level of cyclin F is regulated during the cell cycle is completely obscure. Here we show that, similar to cyclin A, cyclin F is degraded when the spindle assembly checkpoint is activated and accumulates when the DNA damage checkpoint is activated. Cyclin F is a very unstable protein throughout much of the cell cycle. Unlike other cyclins, degradation of cyclin F is independent of ubiquitination and proteasome-mediated pathways. Interestingly, proteolysis of cyclin F is likely to involve metalloproteases. Rapid destruction of cyclin F does not require the N-terminal F-box motif but requires the COOH-terminal PEST sequences. The PEST region alone is sufficient to interfere with the degradation of cyclin F and confer instability when fused to cyclin A. These data show that although cyclin F is degraded at similar time as the mitotic cyclins, the underlying mechanisms are entirely distinct.Cyclins and cyclin-dependent kinases (CDKs) 1 are key regulators of the eukaryotic cell cycle. In mammalian cells, different cyclin-CDK complexes are involved in regulating different cell cycle transitions: cyclin D-CDK4/6 for G 1 progression, cyclin E-CDK2 for the G 1 -S transition, cyclin A-CDK2 for S phase progression, and cyclin A/B-CDC2 for entry into M phase (1). Apart from these well known roles in the cell cycle, several cyclins and CDKs are involved in processes not directly related to the cell cycle. Cyclin D can bind and activate the estrogen receptor, and CDK5 is activated in postmitotic neurons by p35. The cyclin H-CDK7 complex is a component of both the CDKactivating kinase and the basal transcription factor TFIIH and can phosphorylate CDKs and the carboxyl-terminal repeat domain of the large subunit of RNA polymerase II, respectively.

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Regulation of Cyclin A-Cdk2 by SCF Component Skp1 and F-Box Protein Skp2

Cited by 72 publications

References 37 publications

Deregulated degradation of the cdk inhibitor p27 and malignant transformation

Deregulated degradation of the cdk inhibitor p27 and malignant transformation

Generation of an indestructible cyclin B1 by caspase-6-dependent cleavage during mitotic catastrophe

Cyclin F Is Degraded during G2-M by Mechanisms Fundamentally Different from Other Cyclins

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