A Proinflammatory Cytokine Inhibits P53 Tumor Suppressor Activity

Abstract

p53 has a key role in the negative regulation of cell proliferation, in the maintenance of genomic stability, and in the suppression of transformation and tumorigenesis. To identify novel regulators of p53, we undertook two functional screens to isolate genes which bypassed either p53-mediated growth arrest or apoptosis. In both screens, we isolated cDNAs encoding macrophage migration inhibitory factor (MIF), a cytokine that was shown previously to exert both local and systemic proinflammatory activities. Treatment with MIF overcame p53 activity in three different biological assays, and suppressed its activity as a transcriptional activator. The observation that a proinflammatory cytokine, MIF, is capable of functionally inactivating a tumor suppressor, p53, may provide a link between inflammation and tumorigenesis.

MIF loss impairs Myc-induced lymphomagenesis

“…[20][21][22] Several studies have indicated that activation of cell proliferation by MIF is due to a functional inactivation of the p53 tumor suppressor. 17,18,23 Thus, MIF overexpression extends the lifespan of primary cells in vitro, inhibits Myc-induced p53-dependent apoptosis, and protects macrophages from NO-induced apoptosis. 17 Conversely, when MIF is lost, cell survival and functions are compromised in a p53-dependent manner.…”

“…17,18,23 Thus, MIF overexpression extends the lifespan of primary cells in vitro, inhibits Myc-induced p53-dependent apoptosis, and protects macrophages from NO-induced apoptosis. 17 Conversely, when MIF is lost, cell survival and functions are compromised in a p53-dependent manner. 17,18 It has been proposed that this functional suppression of p53 by MIF is based on interference with p53-dependent transcriptional activity.…”

“…10,11 Moreover, based on the observed correlation of MIF expression levels and clinical aggressiveness of tumors, [12][13][14][15][16] it was suggested that MIF could serve as a connection between inflammation and cancer. 17,18 However, the process by which MIF exerts its effect on target cells is not understood.…”

“…17 Conversely, when MIF is lost, cell survival and functions are compromised in a p53-dependent manner. 17,18 It has been proposed that this functional suppression of p53 by MIF is based on interference with p53-dependent transcriptional activity. 17,18 Accordingly, upregulation of MIF at sites of chronic inflammation might impair p53-dependent cellular responses towards DNA damage, and thus promote the accumulation of oncogenic mutations.…”

“…17,18 It has been proposed that this functional suppression of p53 by MIF is based on interference with p53-dependent transcriptional activity. 17,18 Accordingly, upregulation of MIF at sites of chronic inflammation might impair p53-dependent cellular responses towards DNA damage, and thus promote the accumulation of oncogenic mutations. 17 We previously showed that primary fibroblasts derived from MIF-deficient mice exhibit E2F-and p53-dependent growth defects and reduced susceptibility to oncogenic transformation.…”