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MIF coordinates the cell cycle with DNA damage checkpoints. Lessons from knockout mouse models.

Fingerle-Rowson G, Petrenko O - Cell Div (2007)

Bottom Line: We have produced compelling evidence that the effects of MIF on cell survival and tumorigenesis are mediated through overlapping pathways, wherein MIF and p53 functionally antagonize each other in the cell.However, the involvement of MIF in p53 function is secondary to p53-independent mechanisms controlling protein stability, DNA damage checkpoints, and the integrity of the genome.Given the broad spectrum of cell types that normally express MIF and its elevated levels at sites of chronic inflammation, this pathway may be generic for many early stage tumors.

View Article: PubMed Central - HTML - PubMed

Affiliation: University Hospital Cologne, Clinic I of Internal Medicine, Dept. of Hematology and Oncology, Cologne, Germany. g.fingerle-rowson@gmx.de

ABSTRACT
Macrophage migration inhibitory factor (MIF) is a ubiquitously expressed pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. We used a genetic approach to show that deletion of the MIF gene in mice has several major consequences for the proliferative and transforming properties of cells. MIF-deficient cells exhibit increased resistance to oncogenic transformation. The transformation defects associated with MIF deficiency can be overcome through concomitant inactivation of the p53 and Rb/E2F tumor suppressor pathways. We have produced compelling evidence that the effects of MIF on cell survival and tumorigenesis are mediated through overlapping pathways, wherein MIF and p53 functionally antagonize each other in the cell. However, the involvement of MIF in p53 function is secondary to p53-independent mechanisms controlling protein stability, DNA damage checkpoints, and the integrity of the genome. Given the broad spectrum of cell types that normally express MIF and its elevated levels at sites of chronic inflammation, this pathway may be generic for many early stage tumors.

No MeSH data available.


Related in: MedlinePlus

SCF activity is sustained by dynamic cycles of assembly and disassembly. (A). DNA damage checkpoint pathways feed into the proteolytic degradation of key cell cycle regulators, mediated by SCF, to stop the cell cycle. The scheme indicates the elements that make up signal transducers (ATM, ATR, Chk1, Chk2) and effectors (SCF, CSN and 26S proteasome). MIF binds to Jab1/CSN5 and prevents it from interacting with proteins targeted by CSN, notably the Cullins. (B). Multi-subunit structure of the SCF class of E3 ubiquitin ligases. All SCFs consist of Cullins, Skp1, Rbx1 and F-box proteins which associate to form an enzymatically active complex. The posttranslational modification of Cullin (Cul1) by Nedd8 renders SCF active, though unstable. The removal of Nedd8 from Cullin is catalyzed by Jab1/CSN5. Following deneddylation of Cullins, Skp1 and F-box proteins are replaced by the inhibitory protein Cand1.
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Figure 2: SCF activity is sustained by dynamic cycles of assembly and disassembly. (A). DNA damage checkpoint pathways feed into the proteolytic degradation of key cell cycle regulators, mediated by SCF, to stop the cell cycle. The scheme indicates the elements that make up signal transducers (ATM, ATR, Chk1, Chk2) and effectors (SCF, CSN and 26S proteasome). MIF binds to Jab1/CSN5 and prevents it from interacting with proteins targeted by CSN, notably the Cullins. (B). Multi-subunit structure of the SCF class of E3 ubiquitin ligases. All SCFs consist of Cullins, Skp1, Rbx1 and F-box proteins which associate to form an enzymatically active complex. The posttranslational modification of Cullin (Cul1) by Nedd8 renders SCF active, though unstable. The removal of Nedd8 from Cullin is catalyzed by Jab1/CSN5. Following deneddylation of Cullins, Skp1 and F-box proteins are replaced by the inhibitory protein Cand1.

Mentions: Remarkably, a search for intracellular MIF-binding partners by the yeast two-hybrid system yielded Jab1/CSN5 as potential candidate [56]. CSN5 is a component of the COP9/CSN signalosome, a multiprotein complex that plays essential roles in differentiation and morphogenesis [57,58]. Not surprisingly, deletion of individual subunits of the CSN complex is embryonically lethal [59,60]. Also Jab1- embryos die soon after implantation due to impaired proliferation and accelerated apoptosis, and these defects have been attributed in part to the accumulation and/or impaired degradation of p53, cyclin E, and p27 [61]. Importantly, Jab1 possesses an intrinsic metalloprotease activity, which as mentioned above, targets SCF complexes and deconjugates Nedd8 from the cullins [51,58]. Whereas Jab1 recycles neddylated cullins into more stable unneddylated forms [62], the CSN signalosome can further stabilize the SCF by preventing the autoubiquitination of substrate-recruiting F-box proteins [63,64]. However, deneddylated cullins are open to interaction with the inhibitory Cand1, which has the capacity to displace both Skp1 and F-box proteins [53,54]. Therefore, unbalanced activity of Jab1/CSN5 can directly or indirectly block ubiquitin-dependent proteolysis [65]. Conversely, MIF binds to Jab1/CSN5 and prevents it from interacting with proteins targeted by the CSN signalosome [66] (Fig. 2). Our recent study showed that this negative regulation of Jab1/CSN5 by MIF is a physiologic requirement to sustain optimal composition and activity of SCF ubiquitin ligases [9].


MIF coordinates the cell cycle with DNA damage checkpoints. Lessons from knockout mouse models.

Fingerle-Rowson G, Petrenko O - Cell Div (2007)

SCF activity is sustained by dynamic cycles of assembly and disassembly. (A). DNA damage checkpoint pathways feed into the proteolytic degradation of key cell cycle regulators, mediated by SCF, to stop the cell cycle. The scheme indicates the elements that make up signal transducers (ATM, ATR, Chk1, Chk2) and effectors (SCF, CSN and 26S proteasome). MIF binds to Jab1/CSN5 and prevents it from interacting with proteins targeted by CSN, notably the Cullins. (B). Multi-subunit structure of the SCF class of E3 ubiquitin ligases. All SCFs consist of Cullins, Skp1, Rbx1 and F-box proteins which associate to form an enzymatically active complex. The posttranslational modification of Cullin (Cul1) by Nedd8 renders SCF active, though unstable. The removal of Nedd8 from Cullin is catalyzed by Jab1/CSN5. Following deneddylation of Cullins, Skp1 and F-box proteins are replaced by the inhibitory protein Cand1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1941730&req=5

Figure 2: SCF activity is sustained by dynamic cycles of assembly and disassembly. (A). DNA damage checkpoint pathways feed into the proteolytic degradation of key cell cycle regulators, mediated by SCF, to stop the cell cycle. The scheme indicates the elements that make up signal transducers (ATM, ATR, Chk1, Chk2) and effectors (SCF, CSN and 26S proteasome). MIF binds to Jab1/CSN5 and prevents it from interacting with proteins targeted by CSN, notably the Cullins. (B). Multi-subunit structure of the SCF class of E3 ubiquitin ligases. All SCFs consist of Cullins, Skp1, Rbx1 and F-box proteins which associate to form an enzymatically active complex. The posttranslational modification of Cullin (Cul1) by Nedd8 renders SCF active, though unstable. The removal of Nedd8 from Cullin is catalyzed by Jab1/CSN5. Following deneddylation of Cullins, Skp1 and F-box proteins are replaced by the inhibitory protein Cand1.
Mentions: Remarkably, a search for intracellular MIF-binding partners by the yeast two-hybrid system yielded Jab1/CSN5 as potential candidate [56]. CSN5 is a component of the COP9/CSN signalosome, a multiprotein complex that plays essential roles in differentiation and morphogenesis [57,58]. Not surprisingly, deletion of individual subunits of the CSN complex is embryonically lethal [59,60]. Also Jab1- embryos die soon after implantation due to impaired proliferation and accelerated apoptosis, and these defects have been attributed in part to the accumulation and/or impaired degradation of p53, cyclin E, and p27 [61]. Importantly, Jab1 possesses an intrinsic metalloprotease activity, which as mentioned above, targets SCF complexes and deconjugates Nedd8 from the cullins [51,58]. Whereas Jab1 recycles neddylated cullins into more stable unneddylated forms [62], the CSN signalosome can further stabilize the SCF by preventing the autoubiquitination of substrate-recruiting F-box proteins [63,64]. However, deneddylated cullins are open to interaction with the inhibitory Cand1, which has the capacity to displace both Skp1 and F-box proteins [53,54]. Therefore, unbalanced activity of Jab1/CSN5 can directly or indirectly block ubiquitin-dependent proteolysis [65]. Conversely, MIF binds to Jab1/CSN5 and prevents it from interacting with proteins targeted by the CSN signalosome [66] (Fig. 2). Our recent study showed that this negative regulation of Jab1/CSN5 by MIF is a physiologic requirement to sustain optimal composition and activity of SCF ubiquitin ligases [9].

Bottom Line: We have produced compelling evidence that the effects of MIF on cell survival and tumorigenesis are mediated through overlapping pathways, wherein MIF and p53 functionally antagonize each other in the cell.However, the involvement of MIF in p53 function is secondary to p53-independent mechanisms controlling protein stability, DNA damage checkpoints, and the integrity of the genome.Given the broad spectrum of cell types that normally express MIF and its elevated levels at sites of chronic inflammation, this pathway may be generic for many early stage tumors.

View Article: PubMed Central - HTML - PubMed

Affiliation: University Hospital Cologne, Clinic I of Internal Medicine, Dept. of Hematology and Oncology, Cologne, Germany. g.fingerle-rowson@gmx.de

ABSTRACT
Macrophage migration inhibitory factor (MIF) is a ubiquitously expressed pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. We used a genetic approach to show that deletion of the MIF gene in mice has several major consequences for the proliferative and transforming properties of cells. MIF-deficient cells exhibit increased resistance to oncogenic transformation. The transformation defects associated with MIF deficiency can be overcome through concomitant inactivation of the p53 and Rb/E2F tumor suppressor pathways. We have produced compelling evidence that the effects of MIF on cell survival and tumorigenesis are mediated through overlapping pathways, wherein MIF and p53 functionally antagonize each other in the cell. However, the involvement of MIF in p53 function is secondary to p53-independent mechanisms controlling protein stability, DNA damage checkpoints, and the integrity of the genome. Given the broad spectrum of cell types that normally express MIF and its elevated levels at sites of chronic inflammation, this pathway may be generic for many early stage tumors.

No MeSH data available.


Related in: MedlinePlus