SCF-mediated protein degradation and cell cycle control

Ang, Xiaolu L.; Harper, J. Wade

doi:10.1038/sj.onc.1208614

Cited by 175 publications

(138 citation statements)

References 110 publications

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“…Phosphorylation of a single phosphorylatable substrate residue by a kinase may be insufficient for its specific recognition by the degradation machinery, but it could serve to "prime" that of another sequentially or spatially related phosphorylatable residue by the same or a different kinase (87). Thus, multisite phosphorylation would not only serve to signal the modified protein as a target for disposal but also control the precise timing of this event by insuring that it is only targeted when all the relevant sites are phosphorylated (88). Several examples exist of multisite phosphorylation on discrete conserved primary sequence peptide motifs known as phosphodegrons that function in the substrate recognition by one or more E3 Ub ligases of the SCF (complex of SKP1, CUL1, and F-box protein) family (88 -93).…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin-dependent Proteasomal Degradation of Human Liver Cytochrome P450 2E1

Wang

Guan²,

Acharya

et al. 2011

Journal of Biological Chemistry

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Human liver CYP2E1 is a monotopic, endoplasmic reticulumanchored cytochrome P450 responsible for the biotransformation of clinically relevant drugs, low molecular weight xenobiotics, carcinogens, and endogenous ketones. CYP2E1 substrate complexation converts it into a stable slow-turnover species degraded largely via autophagic lysosomal degradation. Substrate decomplexation/withdrawal results in a fast turnover CYP2E1 species, putatively generated through its futile oxidative cycling, that incurs endoplasmic reticulum-associated ubiquitin-dependent proteasomal degradation (UPD). CYP2E1 thus exhibits biphasic turnover in the mammalian liver. We now show upon heterologous expression of human CYP2E1 in Saccharomyces cerevisiae that its autophagic lysosomal degradation and UPD pathways are evolutionarily conserved, even though its potential for futile catalytic cycling is low due to its sluggish catalytic activity in yeast. This suggested that other factors (i.e. post-translational modifications or "degrons") contribute to its UPD. Indeed, in cultured human hepatocytes, CYP2E1 is detectably ubiquitinated, and this is enhanced on its mechanismbased inactivation. Studies in Ubc7p and Ubc5p genetically deficient yeast strains versus corresponding isogenic wild types identified these ubiquitin-conjugating E2 enzymes as relevant to CYP2E1 UPD. Consistent with this, in vitro functional reconstitution analyses revealed that mammalian UBC7/gp78 and UbcH5a/CHIP E2-E3 ubiquitin ligases were capable of ubiquitinating CYP2E1, a process enhanced by protein kinase (PK) A and/or PKC inclusion. Inhibition of PKA or PKC blocked intracellular CYP2E1 ubiquitination and turnover. Here, through mass spectrometric analyses, we identify some CYP2E1 phosphorylation/ubiquitination sites in spatially associated clusters. We propose that these CYP2E1 phosphorylation clusters may serve to engage each E2-E3 ubiquitination complex in vitro and intracellularly.Hepatic cytochromes P450 (P450s) 2 are endoplasmic reticulum (ER)-anchored hemoproteins involved in the metabolism of numerous endo-and xenobiotics. These substrates can modulate P450 content, diversity, and/or function (see Refs. 1, 2 and references therein) through induction via either increased synthesis or protein stabilization, i.e. half-life prolongation (3-9). By contrast, "suicide" substrate/inactivators accelerate the degradation of certain P450s and dramatically curtail their halflives (10 -23). Such substrate-mediated P450 induction and/or enhanced turnover can influence the severity and the time course of certain pharmacokinetic/pharmacodynamic drugdrug interactions and is an important therapeutic consideration (24 -27).P450 turnover has been proposed to involve various proteolytic mechanisms (6 -9, 28 -38). However, it is now increasingly evident that in common with other type I monotopic ER proteins, P450s such as CYPs 3A (both native and structurally inactivated) undergo ER-associated degradation (ERAD) involving the ubiquitin (Ub)-dependent 26 S proteasomal system (UPS) (6 ...

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Section: Discussionmentioning

confidence: 99%

Ubiquitin-dependent Proteasomal Degradation of Human Liver Cytochrome P450 2E1

Wang

Guan²,

Acharya

et al. 2011

Journal of Biological Chemistry

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“…Phosphorylation can act as a mark for ubiquitination, a phenomenon extensively characterized for substrates of the Cullin-containing SCF E3 ubiquitin ligase [31]. Indeed one study in human cells showed that in the presence of the the topoisomerase I poison Camptothecin (CPT), the phosphorylation of Chk1 on S345 by ATR precedes its ubiquitindependent proteolysis by an SCF ligase containing either the Cul1 or Cul4A Cullins [32].…”

Section: Ubiquitin-dependent Proteolysis Of Activated Checkpoint Protmentioning

confidence: 99%

Turning off the G2 DNA damage checkpoint

Calonge

O’Connell

2008

DNA Repair

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In response to DNA damage, cells activate checkpoints to delay cell cycle progression and allow time for completion of DNA repair before commitment to S-phase or mitosis. During G2, many proteins collaborate to activate Chk1, an effector protein kinase that ensures the mitotic cyclindependent kinase remains in an inactive state. This checkpoint is ancient in origin and highly conserved from fission yeast to humans. Work from many groups has led to a detailed description of the spatiotemporal control of signaling events leading to Chk1 activation. However, to survive DNA damage in G2, the checkpoint must be inactivated to allow resumption of cell cycling and entry into mitosis. Though only beginning to be understood, here we review current data regarding checkpoint termination signals acting on Chk1 and its' upstream regulators.

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“…9 Just as the SCF Cdc4 , SCF complexes in mammals regulate the abundance and activity of many proteins involved in regulating cell division, growth, and differentiation. 10,11 …”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Tumor Suppression by the SCFFbw7

Minella¹,

Clurman²

2005

Cell Cycle

106

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SCF ubiquitin ligases regulate the degradation of many proteins involved in the control of cell division and growth. F-box proteins are the SCF components that bind to substrates, and this binding is usually signaled by substrate phosphorylation. The Fbw7/hCdc4 F-box protein was first recognized by its ability to bind cyclin E, and the SCF Fbw7 is now known to target c-Myc, c-Jun and Notch for degradation in addition to its role in cyclin E proteolysis. Fbw7 thus negatively regulates several key oncoproteins. Accordingly, Fbw7 is a tumor suppressor that is mutated in a wide spectrum of human cancers, and Fbw7 functions as a haploinsufficient tumor suppressor in mice. Because there are three Fbw7 isoforms that reside in different subcellular compartments, as well as multiple Fbw7 substrates that are the products of proto-oncogenes, the mechanisms of tumor suppression by Fbw7 are complex and incompletely understood. In this review we discuss the activities of the SCF Fbw7 in the context of its role as a tumor suppressor and highlight recent findings demonstrating that dominant oncogenes disable Fbw7 function.

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SCF-mediated protein degradation and cell cycle control

Cited by 175 publications

References 110 publications

Ubiquitin-dependent Proteasomal Degradation of Human Liver Cytochrome P450 2E1

Ubiquitin-dependent Proteasomal Degradation of Human Liver Cytochrome P450 2E1

Turning off the G2 DNA damage checkpoint

Mechanisms of Tumor Suppression by the SCFFbw7

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