Articles in 2012

The term “lineage reprogramming” is typically used to describe the conversion of one differentiated somatic cell type into another without transit through a pluripotent intermediate. Two recent reports in Nature demonstrate that such a conversion can be achieved in the heart in situ, and suggest a novel, regenerative approach for the development of cardiac therapeutics.

Cap-dependent translation is initiated by the binding of eIF4E to the cap structure at the 5′ end of mRNAs. During hypoxic stress, global translation decreases because eIF4E is inactivated. In a recent article in Nature, Lee and colleagues show that residual hypoxic translation is maintained by a specialized isoform of eIF4E, which binds to target mRNAs in complex with a hypoxia-induced RNP.

One of the two X chromosomes in cells of female mammals is transcriptionally silenced in a process known as X chromosome inactivation (XCI). Initiation of XCI is regulated by the ubiquitin ligase Rnf12/RLIM, but the mechanisms by which Rnf12/RLIM mediates this process has been a mystery. A recent study by Gontan et al. shows that Rnf12/RLIM targets REX1, an inhibitor of XCI, for proteasomal degradation, providing an answer to this question.

Salicylic acid (SA) is widely recognized as a key player in plant immunity. While several proteins have been previously identified as the direct targets of SA, SA-mediated plant defense signaling mechanisms remain unclear. The Nature paper from Xinnian Dong's group demonstrates that the NPR1 paralogues NPR3 and NPR4 directly bind SA, and this binding modulates their interaction with NPR1 and thereby degradation of this key positive regulator of SA-mediated defense, shedding important new insight into the mechanism(s) of SA-mediated, NPR1-dependent plant defense signal transduction.

Secreted proteins play essential roles in every step of cancer metastasis, while the identities and functions of those that contribute to tissue-specific metastasis are largely uncharacterized. Two articles in Cell Research report the discovery and functional analyses of novel secreted proteins that are biologically and clinically relevant to bone metastasis. The combinatory approaches represented here, together with advances in related technology, will promise a better understanding of the cancer secretome.

Adipose tissue remodeling is a dynamic process during nutritional fluctuation that plays critical roles in metabolic homeostasis and insulin sensitivity. The process is highly regulated by many factors, including adipokines and cytokines that are locally released within fat pads. In a recent study published in Nature, Jonker and colleagues identified FGF1 as an important mediator that is selectively induced in fat cells by high-fat diet feeding and established the PPARγ-FGF1 axis as a critical pathway that regulates adipose tissue remodeling and ultimately systemic metabolic homeostasis.

The link between impaired autophagic flux (autophagus interruptus), damaged mitochondria, and myocardial inflammation has been further tightened with the recent paper by Oka and colleagues, in which failure to degrade mitochondrial DNA exacerbated myocardial inflammation in the context of pressure overload. Using mice with cardiac-specific deletion of the lysosomal DNase II that were subjected to aortic banding, Otsu's group showed that mitochondrial DNA accumulated in lysosomes and resulted in TLR9-dependent production of inflammatory cytokines.

Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder often considered to be the third most common muscular dystrophy. Deletions reducing the copy number of the D4Z4 repeat in the distal end of the 4q arm are the main genetic cause of the disease. The recently highlighted research has identified a transcriptional activatory long non-coding RNA involved in the disease that acts through the recruitment of ASH1L, a protein belonging to the Trithorax family.

During fasting, dephosphorylation-dependent activation of the CREB coactivator CRTC2 by glucagon is crucial for activation of the hepatic gluconeogenic program, but the molecular mechanism by which hormones regulate CRTC2 activation remains unclear. A recent report in Nature showed that PKA-dependent phosphorylation of the inositol-1,4,5-trisphosphate receptor (InsP3R) induces Ca²⁺ mobilization, leading to increase in the phosphatase activity of calcineurin and the subsequent dephosphorylation of CRTC2, thereby resulting in the induction of gluconeogenic gene expression. It also showed that insulin-dependent phosphorylation of InsP3R by Akt inhibits Ca²⁺ mobilization and CRTC2 dephosphorylation, resulting in the suppression of gluconeogenesis.

In a recent issue of Nature, Hao et al. report an unexpected link between the secreted stem cell factor/Wnt agonist R-spondin and Wnt receptors through the transmembrane ZNRF3 protein, a RING finger ubiquitin ligase. ZNRF3 acts to turn over Frizzled and LRP6 receptors. R-spondin binds to ZNRF3, in addition to transmembrane LGR4/5 receptors, to antagonize degradation of the Wnt receptors by ZNRF3, thereby resulting in increased Frizzled and LRP6 levels and a greater Wnt response.

Although overlooked for many years, alternative cleavage and polyadenylation (APA) is now emerging as a major mechanism of gene regulation. A recent study identifies poly(A)-binding protein nuclear 1 (PABPN1), a general factor of polyadenylation, as a suppressor of alternative poly(A) sites.

The mammalian target of rapamycin (mTOR) protein kinase regulates a wide variety of cellular processes, including protein synthesis, yet the downstream translational program under the control of mTOR is poorly understood. Two recent studies by Hsieh et al. and Thoreen et al. now start to address this issue, and uncover a subset of genes translationally regulated by oncogenic mTOR signaling that may contribute to tumorigenesis.

Recent progress in the induced pluripotent stem cell (iPSC) field as well as the establishment of germline stem cell isolation and culture methodologies may provide an in vitro platform for the study of physiological and pathological human gamete development and open new avenues for cell replacement-based personalized treatment of infertility.

While many mechanisms have been proposed for microRNAs (miRNAs) function, most ultimately cause message degradation. A view has emerged that miRNAs silence gene expression by promoting the association of mRNA decay factors. Recent research results, however, suggest that in both zebrafish and fruit fly, translational inhibition is the initiating event of miRNA-mediated gene silencing.