FDXR regulates TP73 tumor suppressor via IRP2 to modulate aging and tumor suppression

Abstract

Ferredoxin reductase (FDXR) is a mitochondrial flavoprotein that initiates electron transport from NADPH to several cytochromes P450 via two electron carriers, ferredoxin 1 (FDX1) and FDX2. FDXR is the sole ferredoxin reductase in humans and plays a critical role in steroidogenesis and biosynthesis of heme and iron–sulfur clusters. However, much less is known about the role of FDXR in cancer. Here, we show that FDXR plays a role in tumorigenesis by modulating expression of the tumor suppressor p73. By using genetically modified mouse models, we recently showed that mice deficient in either Fdxr or Trp73 had a shorter lifespan and were prone to spontaneous tumors as compared with wild‐type (WT) mice. Interestingly, compound Trp73 +/−;Fdxr +/− mice lived longer and developed fewer tumors when compared with Fdxr +/− or Trp73 +/− mice. Moreover, we found that cellular senescence was increased in Trp73 +/− and Fdxr +/− mouse embryonic fibroblasts (MEFs), which was further increased in Trp73 +/−;Fdxr +/− MEFs, as compared with that in WT MEFs. As FDXR is regulated by p73, we examined whether there was a feedback regulation between p73 and FDXR. Indeed, we found that Trp73 expression was decreased by loss of Fdxr in MEFs and that FDXR is required for p73 expression in multiple human cancer cell lines independent of p53. Mechanistically, we found that loss of FDXR, via FDX2, increased expression of iron‐binding protein 2 (IRP2), which subsequently repressed TP73 mRNA stability. We also showed that TP73 transcript contained an iron response element in its 3′UTR, which was required for IRP2 to destabilize TP73 mRNA. Together, these data reveal a novel regulation of p73 by FDXR via IRP2 and that the FDXR–p73 axis plays a critical role in aging and tumor suppression. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Deferasirox-Dependent Iron Chelation Enhances Mitochondrial Dysfunction and Restores p53 Signaling by Stabilization of p53 Family Members in Leukemic Cells

“…Interestingly, p53 is known to play a pivotal role in controlling iron homeostasis by direct interaction with Ferredoxin Reductase (FDXR) and Iron Responsive Element Binding Protein 2 (IRP2) proteins [ 20 , 21 , 22 ]. Additionally, iron depletion triggered p53 phosphorylation and stabilization, thus preventing its proteasomal degradation [ 23 , 24 , 25 , 26 ]. Recently, Shen and colleagues demonstrated that intracellular iron overload shortens p53 half-life by promoting p53 nuclear export and cytosolic degradation [ 27 , 28 , 29 ].…”

Small Proline-Rich Protein 2A and 2D Are Regulated by the RBM38-p73 Axis and Associated with p73-Dependent Suppression of Chronic Inflammation

“…Previously, we and others showed that p73-deficient mice are prone to spontaneous tumors along with chronic inflammation in multiple organs [ 4 , 21 ]. Interestingly, mice deficient in Rbm38 are also prone to spontaneous tumors with defects in immune system and have a short lifespan [ 22 , 25 ].…”

“…For Rbm38 −/− mice, 7 of them were generated for this study and 23 of them were generated previously [ 22 ]. For Trp73 +/− mice, 4 of them were generated for this study and 28 were generated previously [ 21 ]. All the mice were derived from the same C57BL/6 background and maintained in the same animal facility.…”

“…Thus, RBM38 and p73 form a feedforward regulatory loop. To understand the biological function of RBM38, we generated a Rbm38 -null mouse model and found that like Trp73 -KO mouse model [ 21 ], Rbm38 −/− mice are prone to spontaneous tumors and chronic inflammation [ 22 ]. As chronic inflammation is closely related to cancer development, we postulate that RBM38 cooperates with p73 to regulate chronic inflammation and tumor suppression.…”

Retrospective analysis ofThe Two Sister Studyusing haplotype-based association testing to identify loci associated with early-onset breast cancer

“…The remaining candidates identified by haplotype trend regression may be broadly categorized in terms of known involvement in cancer, metastasis, and age-of-onset in disease. AGO2 (argonaute 2), CNNM1 (cyclin and CBS domain divalent metal cation transport mediator 1), KIAA1109 , and TP73 (tumor promoter 73) have been implicated in breast cancer, metastasis, and disease age-of-onset ( 49-57 ). The noncoding LINC00941 RNA, LYPD6B (LY6/PLAUR Domain Containing 6B), and PPFIBP1 (liprin-beta-1) have been implicated in cancers that may or may not include breast cancer, have been implicated in metastasis, but have no known association with disease age-of-onset ( 58-61 ).…”