News & Comment

The investigation of virus-induced liver disease and hepatocellular carcinoma needs small animal models modeling hepatitis C virus (HCV) infection and liver disease biology. A recent study published in Cell Research reports a novel mouse model which is permissive for chronic HCV infection and shows chronic liver injury including inflammation, steatosis and fibrosis.

Control of the activity of the microtubule motor cytoplasmic dynein 1 is essential for its function in intracellular transport. A recent paper by McKenney et al. published in Science shows that activation of processive dynein motility requires the formation of cargo adaptor-dynein-dynactin complexes.

Implantation involves complex signaling networks, which direct morphological and molecular transformation of the embryo and the uterus and establish the trajectory of normal pregnancy. The recent work by Zhang et al. published in Cell Research, identifies the transcriptional regulator, Rbpj, as essential for uterine closure and proper embryo alignment during implantation in the mouse, raising the possibility that aberrant Rbpj signaling could contribute to infertility in humans.

When ribosomes encounter upstream open reading frames (uORFs) during scanning of the 5′ untranslated region (5′ UTR), translation of the downstream ORF requires re-initiation. In a recent paper in Nature, Schleich et al. describe metazoan factors which specifically promote re-initiation.

Emerging evidence indicates that there are factors within the blood of young animals that have the ability to restore youthful characteristics to a number of organ systems in older animals. Growth/differentiation factor 11 (GDF11) is the first of such factors to be identified, and two new studies demonstrate that this “factor of youth” rejuvenates stem cells found in the skeletal muscle and brain of aged mice.

The propagation of kinase-mediated phosphorylation signals is central to the oncogenic activity of the RAS-MAPK pathway in human cancers. A recent study shows that protein lysine methylation controls the phosphorylation status of a key component of the RAS-MAPK pathway to enable oncogenic KRAS in cancer progression.

The phosphatidylinositol 3-kinase complex I (PI3K complex I) is a crucial regulator of autophagy, which contains Beclin 1 (or ATG6), ATG14L, VPS34 (or the class III phosphatidylinositol 3-kinase and its adaptor VPS15) and AMBRA1, and controls autophagosome formation. In a paper recently published in Cell Research, Xia et al. report that during nutrient deprivation the ubiquitin E3 ligase RNF2 is recruited to the PI3K complex I, and ubiquitinates AMBRA1 to trigger its degradation and downregulate autophagy.

New findings bring to light a previously unappreciated mechanism involved in the regulation of the oncoprotein MYC. Interesting observations find that the long noncoding RNA (lncRNA) PVT1 is active in controlling levels of MYC through regulation of MYC protein stability.

Pathogenic bacteria secrete effector proteins that target host cell Rho GTPases to manipulate the actin cytoskeleton. A recent study in Nature identifies the Pyrin inflammasome as a sensor of this pathogenic process.

The emerging concept of “molecular barcodes” refers to the dynamic combination of post-translational modifications, often of different nature (e.g., phosphorylation and ubiquitination) that gives rise to multiple forms of a protein which can relay distinct signals throughout a cell. In a recent Cell Research paper by Wang et al., the authors report that a PEST domain-containing tyrosine phosphatase, PTPN18, is able to regulate both phosphorylation and ubiquitination of the HER2 oncogene, barcoding HER2 for increased proteasomal degradation rather than for intracellular trafficking.

Myeloproliferative neoplasms are diseases that arise in the stem cells of the blood. In a recent paper published in Nature, Arranz et al. demonstrated that abrogation of sympathetic nerve fibers reduced bone marrow Nestin⁺ mesenchymal cells, which in turn led to an expansion of hematopoietic stem cells and progression of myeloproliferative neoplasms.

The aryl hydrocarbon receptor (AhR) is an important regulator of the immune response. A report by Puccetti and coworkers describes a regulatory pathway by which L-kynurenine (L-Kyn) produced by tryptophan 2,3-dioxygenase 2 (TDO2) activates AhR in cells of the innate immune system to limit endotoxin-triggered inflammation through a mechanism that involves the non-enzymatic anti-inflammatory activities of indoleamine 2,3-dioxygenase 1 (IDO1).

Ultraviolet radiation (UVR) is a major risk factor for melanoma development, but it has been unclear exactly how UVR leads to melanomagenesis. In a recent publication in Nature, Viros et al. identify TP53/Trp53 as a UVR-target gene in melanoma and show that UVR-induced TP53/Trp53 mutations accelerate BRAF(V600E)-driven melanomagenesis.

Accumulating evidence indicates that the mesenchymal-epithelial transition (MET) and epithelial-mesenchymal transition (EMT) are basic mechanisms for cell fate conversion and may help us understand both physiologic and pathologic processes such as development and carcinogenesis. Here, we further suggest that mammalian cells fall into two grand divisions, mesenchymal or epithelial; interconversions between these two grand divisions through EMT/MET resonate with some ancient Chinese philosophic ideas.