Hepatic loss protects mice from non-alcoholic fatty liver disease through lipid metabolic rewiring.

Non-alcoholic fatty liver disease (NAFLD) is the most pervasive liver pathology worldwide. Here, we demonstrate that the ubiquitin E3 ligase Huwe1 is vital in NAFLD pathogenesis. Using mass spectrometry and RNA sequencing, we reveal that liver-specific deletion of Huwe1 () in 1-year-old mice (approximately middle age in humans) elicits extensive lipid metabolic reprogramming that involves downregulation of lipogenesis and fatty acid uptake, upregulation of fatty acid β-oxidation, and increased oxidative phosphorylation.

The Role of CD36 in Cancer Progression and Its Value as a Therapeutic Target.

Cluster of differentiation 36 (CD36) is a cell surface scavenger receptor that plays critical roles in many different types of cancer, notably breast, brain, and ovarian cancers. While it is arguably most well-known for its fatty acid uptake functions, it is also involved in regulating cellular adhesion, immune response, and apoptosis depending on the cellular and environmental contexts. Here, we discuss the multifaceted role of CD36 in cancer biology, such as its role in mediating metastasis, drug resistance, and immune evasion to showcase its potential as a therapeutic target.

Predicting clinical outcomes of cancer patients with a p53 deficiency gene signature.

The tumor suppressor p53, encoded by the TP53 gene, is mutated or nullified in nearly 50% of human cancers. It has long been debated whether TP53 mutations can be utilized as a biomarker to predict clinical outcomes of cancer patients. In this study, we applied computational methods to calculate p53 deficiency scores (PDSs) that reflect the inactivation of the p53 pathway, instead of TP53 mutation status.

Macromolecular Crowding: a Hidden Link Between Cell Volume and Everything Else.

High density of intracellular macromolecules creates a special condition known as macromolecular crowding (MC). One well-established consequence of MC is that only a slight change in the concentration of macromolecules (e.g.

X-Linked Is Essential for Oocyte Maturation and Preimplantation Embryo Development.

HUWE1 is a HECT-domain ubiquitin E3 ligase expressed in various tissues. Although HUWE1 is known to promote degradation of the tumor suppressor p53, given a growing list of its substrates, functions of HUWE1 remain elusive. Here, we investigated the role of HUWE1 in the female reproductive system.

Fatty acid-like Pt(IV) prodrugs overcome cisplatin resistance in ovarian cancer by harnessing CD36.

Resistance to the platinum-based chemotherapy drug, cisplatin, is a significant setback in ovarian cancer. We engineered fatty acid-like Pt(iv) prodrugs that harness the fatty acid transporter CD36 to facilitate their entry to ovarian cancer cells. We show that these novel constructs effectively kill cisplatin-resistant ovarian cancer cells.

The protein YWHAE (14-3-3 epsilon) in spermatozoa is essential for male fertility.

Background: Spermatogenesis is a complex biological process highlighted by synthesis and activation of proteins that regulate meiosis and cellular differentiation occur during spermatogenesis. 14-3-3 proteins are adaptor proteins that play critical roles in kinase signaling, especially for regulation of cell cycle and apoptosis in eukaryotic cells. There are seven isoforms of the 14-3-3 family proteins encoded by seven genes (β, ε, γ, η, θ/τ, ζ and σ).

Engineering liposomal nanoparticles of cholesterol-tethered amphiphilic Pt(iv) prodrugs with prolonged circulation time in blood.

Cisplatin is a platinum-based chemotherapeutic agent widely used in the treatment of various solid tumors. However, a major challenge in the use of cisplatin and in the development of cisplatin derivatives, namely Pt(iv) prodrugs, is their premature reduction in the bloodstream before reaching cancer cells. To circumvent this problem, we designed liposomal nanoparticles coupled with a cholesterol-tethered amphiphilic Pt(iv) prodrug.

Lipid metabolic reprogramming as an emerging mechanism of resistance to kinase inhibitors in breast cancer.

Breast cancer is one of the leading causes of death in women in the United States. In general, patients with breast cancer undergo surgical resection of the tumor and/or receive drug treatment to kill or suppress the growth of cancer cells. In this regard, small molecule kinase inhibitors serve as an important class of drugs used in clinical and research settings.

CD36: a key mediator of resistance to HER2 inhibitors in breast cancer.

Acquired resistance to anti-HER2 therapy is a significant clinical challenge in breast cancer. We recently discovered that during acquisition of resistance to HER2 inhibition, upregulation of the fatty acid transporter CD36 takes place, playing a key role in metabolic rewiring and resistance to anti-HER2 therapy.

Regulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway.

The tumor suppressor p53 and its homologues, p63 and p73, play a pivotal role in the regulation of the DNA damage response, cellular homeostasis, development, aging, and metabolism. A number of mouse studies have shown that a genetic defect in the p53 family could lead to spontaneous tumor development, embryonic lethality, or severe tissue abnormality, indicating that the activity of the p53 family must be tightly regulated to maintain normal cellular functions. While the p53 family members are regulated at the level of gene expression as well as post-translational modification, they are also controlled at the level of protein stability through the ubiquitin proteasomal pathway.

CD36-Mediated Metabolic Rewiring of Breast Cancer Cells Promotes Resistance to HER2-Targeted Therapies.

Although it is established that fatty acid (FA) synthesis supports anabolic growth in cancer, the role of exogenous FA uptake remains elusive. Here we show that, during acquisition of resistance to HER2 inhibition, metabolic rewiring of breast cancer cells favors reliance on exogenous FA uptake over de novo FA synthesis. Through cDNA microarray analysis, we identify the FA transporter CD36 as a critical gene upregulated in cells with acquired resistance to the HER2 inhibitor lapatinib.

Direct regulation of Chk1 protein stability by E3 ubiquitin ligase HUWE1.

The HECT E3 ubiquitin ligase HUWE1 is required for a wide array of important functions in cell biology. Although HUWE1 is known to play a role in DNA damage signaling, the mechanism(s) that underlie this function remain elusive. HUWE1 regulates effectors of DNA replication and genotoxic stress tolerance.

Inverse association between MDM2 and HUWE1 protein expression levels in human breast cancer and liposarcoma.

The ubiquitin E3 ligase MDM2 is best known for its ability to suppress the tumor suppressor p53. However, MDM2 also targets other proteins for proteasomal degradation and accumulating evidence strongly suggests p53-independent roles of MDM2 in cancer. We previously reported that MDM2 promotes degradation of another ubiquitin E3 ligase HUWE1 by ubiquitination, particularly, which confers HER2 breast cancer cells resistance to the HER2 inhibitor lapatinib.

Regulation of MDM2 Stability After DNA Damage.

Cells in our body are constantly exposed to various stresses and threats to their genomic integrity. The tumor suppressor protein p53 plays a critical role in successful defense against these threats by inducing apoptotic cell death or cell cycle arrest. In unstressed conditions, p53 levels and activity must be kept low to prevent lethal activation of apoptotic and senescence pathways.

Automated, quantitative analysis of histopathological staining in nuclei.

Technological advances have allowed the generation of high-throughput imaging of tissue sections. However, the analysis of these samples is typically still performed manually by one or multiple pathologists. We present a novel statistical model for the automated, quantitative analysis of these images.

Receptor tyrosine kinase ERBB4 mediates acquired resistance to ERBB2 inhibitors in breast cancer cells.

Approximately 25% of breast cancers overexpress and depend on the receptor tyrosine kinase ERBB2, one of 4 ERBB family members. Targeted therapies directed against ERBB2 have been developed and used clinically, but many patients continue to develop resistance to such therapies. Although much effort has been focused on elucidating the mechanisms of acquired resistance to ERBB2-targeted therapies, the involvement of ERBB4 remains elusive and controversial.

Metabolic activation of CaMKII by coenzyme A.

Active metabolism regulates oocyte cell death via calcium/calmodulin-dependent protein kinase II (CaMKII)-mediated phosphorylation of caspase-2, but the link between metabolic activity and CaMKII is poorly understood. Here we identify coenzyme A (CoA) as the key metabolic signal that inhibits Xenopus laevis oocyte apoptosis by directly activating CaMKII. We found that CoA directly binds to the CaMKII regulatory domain in the absence of Ca(2+) to activate CaMKII in a calmodulin-dependent manner.

Evading apoptosis in cancer.

Carcinogenesis is a mechanistically complex and variable process with a plethora of underlying genetic causes. Cancer development comprises a multitude of steps that occur progressively starting with initial driver mutations leading to tumorigenesis and, ultimately, metastasis. During these transitions, cancer cells accumulate a series of genetic alterations that confer on the cells an unwarranted survival and proliferative advantage.

A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53.

In the intrinsic pathway of apoptosis, cell-damaging signals promote the release of cytochrome c from mitochondria, triggering activation of the Apaf-1 and caspase-9 apoptosome. The ubiquitin E3 ligase MDM2 decreases the stability of the proapoptotic factor p53. We show that it also coordinated apoptotic events in a p53-independent manner by ubiquitylating the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1.

Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells.

Increased understanding of the precise molecular mechanisms involved in cell survival and cell death signaling pathways offers the promise of harnessing these molecules to eliminate cancer cells without damaging normal cells. Tyrosine kinase oncoproteins promote the genesis of leukemias through both increased cell proliferation and inhibition of apoptotic cell death. Although tyrosine kinase inhibitors, such as the BCR-ABL inhibitor imatinib, have demonstrated remarkable efficacy in the clinic, drug-resistant leukemias emerge in some patients because of either the acquisition of point mutations or amplification of the tyrosine kinase, resulting in a poor long-term prognosis.

[Polio virus detection in stool by the pathogen surveillance system of Japan. An observational study].

Objectives: To examine the applicability of data on polio virus detection in stool by the Pathogen Surveillance System of Japan (PSSJ) for the evaluation of polio virus retention status in a regional community after oral polio vaccination (OPV).

Methods: (1) Data for the city of Kobe (part of the PSSJ data): Cases of polio virus detection in stool reported to Kobe City Public Health Center from January 1, 2000 to June 30, 2010 were examined regarding time duration from vaccination to detection as well as age and gender. (2) PSSJ data: Cases of polio virus detection in stool reported to PSSJ from January 1, 2000 to December 31, 2010 were examined regarding the serological types of the virus as well as age and gender.