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Updated: Apr 28, 2026
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
MIF family members cooperatively inhibit p53 expression and activity
Stephanie E Brock1, Beatriz E Rendon1, Dan Xin1
1Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America.
Abstract:
The tumor suppressor p53 is induced by genotoxic stress in both normal and transformed cells and serves to transcriptionally coordinate cell cycle checkpoint control and programmed cell death responses. Macrophage migration inhibitory factor (MIF) is an autocrine and paracrine acting cytokine/growth factor that promotes lung adenocarcinoma cell motility, anchorage-independence and neo-angiogenic potential. Several recent studies indicate that the only known homolog of MIF, D-dopachrome tautomerase (D-DT - also referred to as MIF-2), has functionally redundant activities with MIF and cooperatively promotes MIF-dependent pro-tumorigenic phenotypes. We now report that MIF and D-DT synergistically inhibit steady state p53 phosphorylation, stabilization and transcriptional activity in human lung adenocarcinoma cell lines. The combined loss of MIF and D-DT by siRNA leads to dramatically reduced cell cycle progression, anchorage independence, focus formation and increased programmed cell death when compared to individual loss of MIF or D-DT. Importantly, p53 mutant and p53 null lung adenocarcinoma cell lines were only nominally rescued from the cell growth effects of MIF/D-DT combined deficiency suggesting only a minor role for p53 in these transformed cell growth phenotypes. Finally, increased p53 activation was found to be independent of aberrantly activated AMP-activated protein kinase (AMPK) that occurs in response to MIF/D-DT-deficiency but is dependent on reactive oxygen species (ROS) that mediate aberrant AMPK activation in these cells. Combined, these findings suggest that both p53 wildtype and mutant human lung adenocarcinoma tumors rely on MIF family members for maximal cell growth and survival.
Insights
Macrophage migration inhibitory factor (MIF) and its homolog D-dopachrome tautomerase (D-DT) suppress tumor suppressor p53 activity in lung cancer. Loss of MIF and D-DT inhibits cancer cell growth and survival, regardless of p53 status.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The tumor suppressor p53 is crucial for cell cycle control and programmed cell death.
- Macrophage migration inhibitory factor (MIF) and its homolog D-dopachrome tautomerase (D-DT) promote lung adenocarcinoma progression.
- MIF and D-DT exhibit functionally redundant activities, enhancing tumor-promoting phenotypes.
Purpose of the Study:
- To investigate the synergistic effect of MIF and D-DT on p53 activity in lung adenocarcinoma.
- To determine the role of MIF and D-DT in regulating lung cancer cell growth and survival.
- To elucidate the signaling pathways involved in MIF/D-DT-mediated regulation of p53.
Main Methods:
- Utilized siRNA to deplete MIF and D-DT in human lung adenocarcinoma cell lines.
- Assessed p53 phosphorylation, stabilization, and transcriptional activity.
- Evaluated cell cycle progression, anchorage independence, focus formation, and programmed cell death.
- Investigated the involvement of AMP-activated protein kinase (AMPK) and reactive oxygen species (ROS).
Main Results:
- MIF and D-DT synergistically inhibit p53 phosphorylation, stabilization, and transcriptional activity.
- Combined depletion of MIF and D-DT significantly reduces cell cycle progression, anchorage independence, and focus formation, while increasing programmed cell death.
- p53 status (wildtype, mutant, or null) had a minor impact on the cell growth effects of MIF/D-DT deficiency.
- p53 activation upon MIF/D-DT deficiency is independent of AMPK but dependent on ROS.
Conclusions:
- MIF and D-DT are critical for the maximal growth and survival of both p53 wildtype and mutant lung adenocarcinoma cells.
- Targeting MIF family members may represent a therapeutic strategy for lung adenocarcinoma.
- The findings highlight a novel mechanism by which MIF and D-DT regulate p53 and promote tumor progression.
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