Troglitazone inhibits cell proliferation by attenuation of epidermal growth factor receptor signaling independent of peroxisome proliferator-activated receptor γ

Peroxisome proliferator-activated receptors （PPAR） belong to the nuclear hormone receptor superfamily of ligand-dependent transcription factors. Recent results have shown that agonists of PPARy, such as troglitazone （TGZ）, can inhibit cell proliferation and promote cell differentiation independent of PPARy. In the present study, we provide evidence that TGZ may bind directly to EGFR and trigger its signaling and internalization independent of PPARγ. Detailed studies revealed that prolonged incubation with TGZ effectively attenuated EGFR signaling by targeting the receptor to the endo-lysosomal degradation machinery. Although the extracellular signal-regulated kinasesignaling pathway was transiently activated by TGZ in EGFR overexpressing cancer cells, inhibition of EGF-induced Akt phosphorylation most likely accounted for the growth arrest of tumor cells caused by TGZ at pharmacologically achievable concentrations. Therefore, we have provided a new line of evidence indicating that TGZ inhibits cell pro- liferation by promoting EGFR degradation and attenuating Akt phosphorylation.

Mitochondria-mediated apoptosis in mammals

The mitochondria-mediated caspase activation pathway is a major apoptotic pathway characterized by mitochondrial outer membrane permeabilization （MOMP） and subsequent release of cytochrome c into the cytoplasm to activate caspases. MOMP is regulated by the Bcl-2 family of proteins. This pathway plays important roles not only in normal development, main- tenance of tissue homeostasis and the regulation of immune system, but also in human diseases such as immune disorders, neurodegeneration and cancer. In the past decades the molecular basis of this pathway and the regulatory mechanism have been comprehen- sively studied, yet a great deal of new evidence indi- cates that cytochrome c release from mitochondria does not always lead to irreversible cell death, and that caspase activation can also have non-death functions. Thus, many unsolved questions and new challenges are still remaining. Furthermore, the dysfunction of this pathway involved in cancer development is obvious, and targeting the pathway as a therapeutic strategy has been extensively explored, but the efficacy of the tar- geted therapies is still under development. In this review we will discuss the mitochondria-mediated apoptosis pathway and its physiological roles and therapeutic implications.

Pairwise distance-based heteroscedasticity test for regressions

In this study,we propose nonparametric testing for heteroscedasticity in nonlinear regression models based on pairwise distances between points in a sample.The test statistic can be formulated such that Ustatistic theory can be applied to it.Although the limiting null distribution of the statistic is complicated,we can derive a computationally feasible bootstrap approximation for such a distribution;the validity of the introduced bootstrap algorithm is proven.The test can detect any local alternatives that are different from the null at a nearly optimal rate in hypothesis testing.The convergence rate of this test statistic does not depend on the dimension of the covariates,which significantly alleviates the impact of dimensionality.We provide three simulation studies and a real-data example to evaluate the performance of the test and demonstrate its applications.

Unc-51-like kinase(ULK)complex-independent autophagy induced by hypoxia

Dear Editor,Macroautophagy(referred to as autophagy herein)is an evolutionarily con served,lysosomal degradatio n process by which cells rid themselves of aggregated proteins and damaged organelles(He and Klionsky,2009).This process involves a finely orchestrated molecular pathway comprising a plethora of ATG proteins essential for autophagosome formation.The mammalian Unc-51-like kinase(ULK)complex plays an essential role to initiate canonical autophagy pathway by relaying upstream nutrient and stress signals to downstream autophagy machinery(Mizushima,2010;Wong et al.,2013).

11＇-Deoxyverticillin A （C42） promotes autophagy through K-Ras/GSK3 signaling pathway in HCT116 cells

Dear Editor Macroautophagy （hereafter referred to as autophagy） is a cellular adaptation to starvation, involving the vesicular sequestration of the long-lived cytoplasmic proteins and organelles such as mitochondria （Klionsky and Emr, 2000）. However, it also results in cell death when overacUvated （Edinger and Thompson, 2004）. Stresses which affect cel- lular homeostasis including changes in oxidation status, build-up of damaged organelles and misfolded proteins, and infection by pathogens, have also been shown to induce autophagy （Rabinowitz and White, 2010）. Besides, autoph- agy was found to be involved in cancer formation and pro- gression. Depending on tumor type, stage, and cellular context, autophagy can play either anti- or pro-tumorigenic roles （Mancias and Kimmelman, 2011）.

NONPARAMETRIC REGRESSION UNDER DOUBLE-SAMPLING DESIGNS

This paper studies nonparametric estimation of the regression function with surrogate outcome data under double-sampling designs, where a proxy response is observed for the full sample and the true response is observed on a validation set. A new estimation approach is proposed for estimating the regression function. The authors first estimate the regression function with a kernel smoother based on the validation subsample, and then improve the estimation by utilizing the information on the incomplete observations from the non-validation subsample and the surrogate of response from the full sample. Asymptotic normality of the proposed estimator is derived. The effectiveness of the proposed method is demonstrated via simulations.

Animal genes identification and mTOR signaling reactivation in autophagy

Autophagy(self-eating)is a self-degradation process essential for survival,differentiation,development,and homeostasis.Conceiving that a process of cellular self-eating could be beneficial may appear bewildering.In its simplest form,however,autophagy is probably a single cell’s adjustment to starvation;the cell is forced to break down part of its own reserves to keep alive until circumstances improve(Mizushima and Klionsky,2007).Based on its mechanism,physiological function,and cargo specificity,autophagy can be classified into at least three forms,chaperone-mediated autophagy,microautophagy,and macroautophagy(Klionsky,2005),among which macroautophagy is the best characterized.Autophagy was discovered in mammalian cells and has been extensively investigated in yeast(Huang and Klionsky,2002).Original studies in yeast Saccharomyces cerevisiae identified a group of autophagy(ATG)genes that are required for survival during starvation(Klionsky et al.,2003).Accumulating evidence indicates that many ATG genes are functionally conserved from yeast to mammals;nevertheless,autophagy is more complicated in multicellular organisms and probably requires factors that are absent in yeast.Until now,little is known about the mechanism of autophagy specific to mammals.In a groundbreaking investigation,Tian et al.(2010)discovered four novel genes particularly required for autophagy in multicellular organisms,and established Caenorhabditis elegans as one of the premier genetic models for uncovering new autophagy genes.The authors also isolated numerous new mutations in genes homologous to yeast autophagy genes,which confirmed the results of the study.These new mutations not only provide a valuable resource for inquiring the structure and function of autophagy proteins,but also set up C.elegans as a preeminent system for investigating the role and regulation of autophagy in multicellular organisms.