Impaired DNA damage checkpoint response in MIF-deficient mice

Abstract

Recent studies demonstrated that proinflammatory migration inhibitory factor(MIF) blocks p53-dependent apoptosis and interferes with the tumor suppressor activity of p53. To explore the mechanism underlying this MIF-p53 relationship, we studied spontaneous tumorigenesis in genetically matched p53-/- and MIF-/-p53-/- mice. We show that the loss of MIF expression aggravates the tumor-prone phenotype of p53-/- mice and predisposes them to a broader tumor spectrum, including B-cell lymphomas and carcinomas. Impaired DNA damage response is at the root of tumor predisposition of MIF-/-p53-/- mice. We provide evidence that MIF plays a role in regulating the activity of Cul1-containing SCF ubiquitin ligases. The loss of MIF expression uncouples Chk1/Chk2-responsive DNA damage checkpoints from SCF-dependent degradation of key cell-cycle regulators such as Cdc25A, E2F1 and DP1, creating conditions for the genetic instability of cells. These MIF effects depend on its association with the Jab1/CSN5 subunit of the COP9/CSN signalosome. Given that CSN plays a central role in the assembly of SCF complexes in vivo, regulation of Jab1/CSN5 by MIF is required to sustain optimal composition and function of the SCF complex.

Macrophage Migration Inhibitory Factor Coordinates DNA Damage Response with the Proteasomal Control of the Cell Cycle

“…Indeed, we found that in MIF-deficient cells a large proportion of Cul1 was deneddylated and therefore remained sequestered by inhibitory Cand1. 43 We also showed that DNA damage and stalled replication e also showed that DNA damage and stalled replication DNA damage and stalled replication induce coordinate activity of Chk1 and the SCF complex in wild type cells. This is achieved by a direct phosphorylation of Cul1 by Chk1.…”

“…This important step of Cul1 activation is severely impaired in MIF-deficient cells. 43 Collectively, these data imply that regulation of Jab1 by MIF is required to sustain a pool of SCF that is devoid of interaction with inhibitory Cand1 but instead is available for interaction with Chk1 but instead is available for interaction with Chk1 (Fig. 1).…”

“…To this end, we compared the DNA damage response in lymphoma cells derived from p53 -/-and MIF -/-p53 -/-mice. 43 Strikingly, MIF/p53 double deficient cells clearly possessed a dysfunctional G 2 M checkpoint, since they continued to proliferate under conditions of DNA damage, which coincided with sharply increased rates of apoptosis. Thus, apparently one essential function of MIF was not to merely promote cell survival, but also to coordinate a second line of cellular defence against DNA damageafter the protective p53 barrier had been eliminated.…”

“…42 Our own recent study showed that this regulation of Jab1 by MIF is a physiologic requirement to sustain optimal composition and activity of SCF ubiquitin ligases, which are known to play a pivotal role in the regulation of cellular responses to DNA damage. 43 …”

“…43 Moreover, Moreover, MIF-deficiency imposes similar defects on the proper degradation of several other important cell cycle regulators such as Cyclin A2, several other important cell cycle regulators such as Cyclin A2, Cyclin A2, E2F1 and DP1. 43 Because MIF directly binds to Jab1 and prevents it from interacting with proteins targeted by CSN, notably the cullins, it appeared that the unrestricted deneddylating activity of Jab1 and therefore the ensuing dysfunction of SCF were collectively responsible for the defects seen in MIF-deficient cells. Indeed, we found that in MIF-deficient cells a large proportion of Cul1 was deneddylated and therefore remained sequestered by inhibitory Cand1.…”