Ferredoxin 2 Is Critical for Tumor Suppression and Lipid Homeostasis but Dispensable for Embryonic Development.

Ferredoxin 1 and 2 (FDX1/2) constitute an evolutionarily conserved FDX family of iron-sulfur cluster-containing proteins. FDX1/2 are cognate substrates of ferredoxin reductase and serve as conduits for electron transfer from NADPH to a set of proteins involved in biogenesis of corticosteroids, hemes, iron-sulfur cluster, and lipoylated proteins. Recently, we showed that Fdx1 is essential for embryonic development and lipid homeostasis.

Ferredoxin 1 is essential for embryonic development and lipid homeostasis.

Mammalian ferredoxin 1 and 2 (FDX1/2) belong to an evolutionary conserved family of iron-sulfur cluster containing proteins and act as electron shutters between ferredoxin reductase (FDXR) and numerous proteins involved in critical biological pathways. FDX1 is involved in biogenesis of steroids and bile acids, Vitamin A/D metabolism, and lipoylation of tricarboxylic acid (TCA) cycle enzymes. FDX1 has been extensively characterized biochemically but its role in physiology and lipid metabolism has not been explored.

Burden of liver cancer due to hepatitis C from 1990 to 2019 at the global, regional, and national levels.

Background: Liver cancer due to hepatitis C (LCDHC) is one of the leading causes of cancer-related deaths worldwide, and the burden of LCDHC is increasing. We aimed to report the burden of LCDHC at the global, regional, and national levels in 204 countries from 1990 to 2019, stratified by etiology, sex, age, and Sociodemographic Index.

Methods: Data on LCDHC were available from the Global Burden of Disease, Injuries, and Risk Factors (GBD) study 2019.

Isoform-specific disruption of the gene reveals a critical role for TAp73γ in tumorigenesis via leptin.

a member of the p53 family, is expressed as TAp73 and ΔNp73 along with multiple C-terminal isoforms (α-η). ΔNp73 is primarily expressed in neuronal cells and necessary for neuronal development. Interestingly, while TAp73α is a tumor suppressor and predominantly expressed in normal cells, TAp73 is found to be frequently altered in human cancers, suggesting a role of TAp73 C-terminal isoforms in tumorigenesis.

Identification of a First-in-Class Small-Molecule Inhibitor of the EIF4E-RBM38 Complex That Enhances Wild-type TP53 Protein Translation for Tumor Growth Suppression.

EIF4E, an mRNA cap-binding protein, is necessary for cap-dependent translation. Overexpression of EIF4E is known to promote cancer development by preferentially translating a group of oncogenic mRNAs. Thus, 4EGI-1, a disruptor of EIF4E-EIF4G1 interaction, was developed to inhibit oncoprotein expression for cancer therapy.

TP73 Isoform-specific disruption reveals a critical role of TAp73beta in growth suppression and inflammatory response.

TP73 is expressed as multiple N- and C-terminal isoforms through two separate promoters or alternative splicing. While N-terminal p73 isoforms have been well studied, very little is known about p73 C-terminal isoforms. Thus, CRISPR was used to delete TP73 Exon13 (E13-KO) to induce p73α to p73β isoform switch.

The RNA-binding protein RBM24 regulates lipid metabolism and SLC7A11 mRNA stability to modulate ferroptosis and inflammatory response.

Lipids play a critical role in many cellular processes by serving as structural components of cell membranes or functioning as energy fuel and signaling molecules. The RNA-binding proteins RBM24 and RBM38 share an identical RNA-binding domain and thereby, regulate a group of same targets, such as p21. However, it is not certain whether RBM24 and RBM38 participates in lipid homeostasis.

ZFP14 Regulates Cancer Cell Growth and Migration by Modulating p53 Protein Stability as Part of the MDM2 E3 Ubiquitin Ligase Complex.

Multi-zinc finger proteins that contain a KRAB domain are part of the biggest family of transcription factors in mammals. However, the physiological or pathological functions for the majority of them are unknown. Here, we showed that (also known as ) is a p53 target gene that can be induced upon genotoxic stress in a p53-dependent manner.

Poly zinc finger protein ZFP14 suppresses lymphomagenesis and abnormal inflammatory response via the HOXA gene cluster.

Poly zinc finger proteins (ZFP) that contain a KRAB (Krüppel-associated box) domain represent the largest class of transcription factors in higher organisms, but their roles in development and pathogenesis are largely undefined. ZFP14 (also known as ZNF531) contains thirteen zinc fingers and is highly conserved across species. Notably, we found that ZFP14 is frequently down-regulated in a multitude of human cancers, which correlates with poor prognosis of patients.

Optimization of eIF4E-Binding Peptide Pep8 to Disrupt the RBM38-eIF4E Complex for Induction of p53 and Tumor Suppression.

Interaction of RNA-binding protein RBM38 with eIF4E on mRNA is known to suppress mRNA translation, which can be disrupted by an 8-amino acid peptide (Pep8-YPYAASPA) derived from RBM38, leading to induction of p53 and tumor suppression. Here, we rationally designed multiple Pep8 derivatives and screened for their binding affinities towards eIF4E We showed that several key residues within Pep8 are necessary for its structure and function. We identified a shortened 7-amino acid peptide (Pep7-PSAASPV) that has the highest affinity towards eIF4E and is the most potent inducer of p53 expression.

Ferredoxin reductase and p53 are necessary for lipid homeostasis and tumor suppression through the ABCA1-SREBP pathway.

p53 is known to modulate metabolism and FDXR is required for steroidogenesis. Given that FDXR is a target/regulator of p53, the FDXR-p53 axis may play a unique role in lipid metabolism. Here, we found that expression of ABCA1, a cholesterol-efflux pump, was suppressed by loss of FDXR and/or p53, leading to activation of master lipogenic regulators SREBP1/2.

The p53 Family: A Role in Lipid and Iron Metabolism.

The p53 family of tumor suppressors, which includes p53, p63, and p73, has a critical role in many biological processes, such as cell cycle arrest, apoptosis, and differentiation. In addition to tumor suppression, the p53 family proteins also participate in development, multiciliogenesis, and fertility, indicating these proteins have diverse roles. In this review, we strive to cover the relevant studies that demonstrate the roles of p53, p63, and p73 in lipid and iron metabolism.

Mice Deficient in the RNA-Binding Protein Zfp871 Are Prone to Early Death and Steatohepatitis in Part through the p53-Mdm2 Axis.

p53 transcription factor is activated upon exposure to various cellular stresses, leading to growth suppression. However, aberrant activation of p53 can lead to defects in embryonic development and other abnormalities. Here, we identified zinc finger protein Zfp871 as a p53 target gene.

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

Small proline-rich protein 2A and 2D (SPRR2A and SPRR2D) provide barrier function in terminally differentiated stratified squamous epithelia through the epidermal differentiation complex. However, little is known how SPRR2A/2D expression is controlled and their role in chronic inflammation. Here, we showed that that SPRR2A/2D expression is controlled by a regulatory loop formed by RNA-binding protein RBM38 and tumor suppressor p73.

Survivin Expression Is Differentially Regulated by a Selective Cross-talk between RBM38 and miRNAs let-7b or miR-203a.

RNA-binding motif 38 (RBM38) is a member of a protein family with a highly conserved RNA-binding motif and has been shown to regulate mRNA processing, stability, and translation. Survivin is an essential modulator of apoptotic and nonapoptotic cell death as well as a stress responder. mRNA is the fourth most frequently overexpressed transcript in the human cancer transcriptome, and its aberrant expression is associated with chemo-/radioresistance and poor prognosis.

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

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.

Iron Regulatory Protein 2 Exerts its Oncogenic Activities by Suppressing TAp63 Expression.

Iron regulatory protein 2 (IRP2) is a key regulator of iron homeostasis and is found to be altered in several types of human cancer. However, how IRP2 contributes to tumorigenesis remains to be elucidated. In this study, we sought to investigate the role of IRP2 in tumorigenesis and found that IRP2 promotes cell growth by repressing TAp63, a member of p53 tumor suppressor family.

PABPN1, a Target of p63, Modulates Keratinocyte Differentiation through Regulation of p63α mRNA Translation.

p63 is expressed from two promoters and produces two N-terminal isoforms, TAp63 and ΔNp63. Alternative splicing creates three C-terminal isoforms p63α, p63β, and p63δ, whereas alternative polyadenylation (APA) in coding sequence creates two more C-terminal isoforms p63γ and p63ε. Although several transcription factors have been identified to differentially regulate the N-terminal p63 isoforms, it is unclear how the C-terminal p63 isoforms are regulated.

Mdm2 is a target and mediator of IRP2 in cell growth control.

Iron is an essential element to all living organisms and plays a vital role in many cellular processes, such as DNA synthesis and energy production. The Mdm2 oncogene is an E3 ligase and known to promote tumor growth. However, the role of Mdm2 in iron homeostasis is not certain.

Mutant p53 antagonizes p63/p73-mediated tumor suppression via Notch1.

p53 is the most frequently mutated gene in human cancers and mutant p53 has a gain of function (GOF) that promotes tumor progression and therapeutic resistance. One of the major GOF activities of mutant p53 is to suppress 2 other p53 family proteins, p63 and p73. However, the molecular basis is not fully understood.

Cancer the'RBP'eutics-RNA-binding proteins as therapeutic targets for cancer.

RNA-binding proteins (RBPs) play a critical role in the regulation of various RNA processes, including splicing, cleavage and polyadenylation, transport, translation and degradation of coding RNAs, non-coding RNAs and microRNAs. Recent studies indicate that RBPs not only play an instrumental role in normal cellular processes but have also emerged as major players in the development and spread of cancer. Herein, we review the current knowledge about RNA binding proteins and their role in tumorigenesis as well as the potential to target RBPs for cancer therapeutics.

A PolH Transcript with a Short 3'UTR Enhances PolH Expression and Mediates Cisplatin Resistance.

Platinum-based anticancer drugs are widely used as a first-line drug for cancers, such as non-small cell lung carcinoma (NSCLC) and bladder cancer. However, the efficacy is limited due to intrinsic or acquired resistance to these drugs. DNA polymerase eta (PolH, Polη) belongs to the Y-family of DNA polymerases and mediates DNA translesion synthesis, a major mechanism for DNA damage tolerance.

Author Correction: Liriodendron genome sheds light on angiosperm phylogeny and species-pair differentiation.

In the Supplementary Information file originally published with this Letter, the authors mistakenly omitted Supplementary Table 14; this has now been amended.

Disruption of the Rbm38-eIF4E Complex with a Synthetic Peptide Pep8 Increases p53 Expression.

Rbm38 is a p53 target and an RNA-binding protein known to suppress p53 translation by preventing eukaryotic translation initiation factor 4E (eIF4E) from binding to p53 mRNA. In this study, we show that synthetic peptides corresponding to the binding interface between Rbm38 and eIF4E, including an 8 amino acid peptide (Pep8) derived from Rbm38, are effective in relieving Rbm38-mediated repression of p53. Molecular simulations showed that Ser-6 in Pep8 forms a hydrogen bond with Asp-202 in eIF4E.

Liriodendron genome sheds light on angiosperm phylogeny and species-pair differentiation.

The genus Liriodendron belongs to the family Magnoliaceae, which resides within the magnoliids, an early diverging lineage of the Mesangiospermae. However, the phylogenetic relationship of magnoliids with eudicots and monocots has not been conclusively resolved and thus remains to be determined. Liriodendron is a relict lineage from the Tertiary with two distinct species-one East Asian (L.