HIF1α delays premature senescence through the activation of MIF

Abstract

Premature senescence in vitro has been attributed to oxidative stress leading to a DNA damage response. In the absence of oxidative damage that occurs at atmospheric oxygen levels, proliferation of untransformed cells continues for extended periods of time. We have investigated the role of the hypoxia-inducible factor 1␣ (HIF1␣) transcription factor in preventing senescence in aerobic and hypoxic conditions. Using embryonic fibroblasts from a conditional HIF1␣ knockout mouse, we found that loss of HIF1␣ under aerobic conditions significantly accelerated the onset of cellular senescence, and decreased proliferation under hypoxia. Furthermore, we identify the macrophage migration inhibitory factor (MIF) as a crucial effector of HIF1␣ that delays senescence. Inhibition of MIF phenocopies loss of HIF1␣. Our findings highlight a novel role for HIF1␣ under aerobic conditions, and identify MIF as a target responsible for this function.Supplemental material is available at http://www.genesdev.org.

Steroid receptor coactivator 3 regulates autophagy in breast cancer cells through macrophage migration inhibitory factor

“…Accordingly, the HIF-1alpha (HIF-1α) transcriptional factor has been reported to induce MIF expression by binding to the HRE of the MIF promoter [18,43]. Similarly, we found that activation of the MIF promoter region (−74 to +127 bp) by HIF-1α is dependent on the presence of a functional HRE but not the CRE, and HIF-1α was recruited to this region of the MIF promoter (Supplementary information, Figure S4).…”

“…It was previously shown that expression of MIF is induced by HIF-1α under hypoxia, and that induction of MIF prevents premature senescence by inactivating the p53 tumor suppressor [18]. Although recent genome-wide analysis of SRC-3 chromatin affinity sites in MCF-7 human breast cancer in response to estrogen induction did not identify the MIF gene, high-stringency HIF-binding site(s) near the MIF gene was identified in another recent genome-wide mapping [42,66].…”

“…Interestingly, both circulating and intracellular levels of MIF were elevated in patients with cancers, and the levels of MIF were closely correlated with tumor aggressiveness and metastatic potential, suggesting that MIF contributed to disease severity and survival [14][15][16][17]. Intracellular MIF interacted with the signalosome component JAB1/CSN5 and was shown to regulate both the activity of tumor suppressor p53 and the angiogenesis induced by hypoxia [17,18]. Interestingly, JAB1/CSN5 was further shown to interact with PR and SRC-1 and potentiated the activity of a variety of transcription factors known to associate with SRC-1, such as AP-1 and NF-κB [19][20][21].…”

Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity

“…Recent studies have shown that cells cultured under hypoxic conditions can acquire the ability to delay the onset of replicative senescence through a mechanism mediated, at least in part, by HIF-1 -dependent up-regulation of hypoxia response element -containing genes such as macrophage migration inhibitory factor (34,35). Although hypoxia may potentially act in a similar fashion to prevent the initiation or maintenance of drug-induced senescence, an alternative mechanism for hypoxia-induced resistance is proposed.…”

Negative Regulation of AMP-activated Protein Kinase (AMPK) Activity by Macrophage Migration Inhibitory Factor (MIF) Family Members in Non-small Cell Lung Carcinomas

“…Prior studies from our laboratory demonstrate that MIF is an important contributor to anchorage independence, cell motility, and invasive potential of A549 lung adenocarcinoma cells (9,10). MIF signals as an extracellular autocrine and paracrine-acting cytokine and is necessary for maximal tumor-associated neovascularization (7,11), evasion from cell senescence (12), and inhibition of the tumor suppressor, p53 (13)(14)(15). Recent studies revealed that the only other known MIF family member, D-dopachrome tautomerase (D-DT), functionally cooperates with, and compensates for, MIF in dictating neoangiogenic potential in human NSCLC cell lines (11).…”