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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2007.10.048 Byline: Deborah L. Berry (1)(2), Eric H. Baehrecke (1)(3) Keywords: CELLBIO; DEVBIO; SIGNALING Abstract: Autophagy is a catabolic process that is negatively regulated by growth and has been implicated in cell death. We find that autophagy is induced following growth arrest and precedes developmental autophagic cell death of Drosophila salivary glands. Maintaining growth by expression of either activated Ras or positive regulators of the class I phosphoinositide 3-kinase (PI3K) pathway inhibits autophagy and blocks salivary gland cell degradation. Developmental degradation of salivary glands is also inhibited in autophagy gene (atg) mutants. Caspases are active in PI3K-expressing and atg mutant salivary glands, and combined inhibition of both autophagy and caspases increases suppression of gland degradation. Further, induction of autophagy is sufficient to induce premature cell death in a caspase-independent manner. Our results provide in vivo evidence that growth arrest, autophagy, and atg genes are required for physiological autophagic cell death and that multiple degradation pathways cooperate in the efficient clearance of cells during development. Author Affiliation: (1) Center for Biosystems Research, University of Maryland Biotechnology Institute, College Park, MD 20742, USA (2) Present address: Children's National Medical Center, Washington, DC 20010, USA (3) Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA Article History: Received 12 June 2007; Revised 7 September 2007; Accepted 16 October 2007 Article Note: (miscellaneous) Published: December 13, 2007

Four genes were identified in a screen for thyroid hormone-induced down-regulation of gene expression in Xenopus laevis tadpole tails. All four encode extracellular glycoproteins that are expressed exclusively in the apical cell layer of the entire tadpole epidermis, which is the equivalent of the mammalian fetal periderm. The onset of the four novel genes' expression late in embryogenesis, their activity throughout the life of the tadpole, their repression by exogenously added thyroid hormone, and the spontaneous cessation of their expression at the end of tadpole life are closely coordinated. These facts suggest that the protein products of these genes form a novel albeit temporary barrier or other structure in the tadpole epidermis that functions in lieu of the cornified, stratified epithelium of the adult epidermis. We have exploited the cloning of these genes for use as cell-specific markers to follow the appearance and loss of apical cells during development. We were able to demonstrate directly that the apical cells are derived from a stratification of the embryonic ectoderm at the onset of the formation of a true epidermis. The apical cells uniformly cover the surface of the tadpole until metamorphosis, when the expression of the four larval epidermis-specific genes is lost coordinately over the entire tadpole. In contrast, the adult epidermis develops with a distinct regional specificity: adult keratin is first expressed up to a line separating the body and tail epidermis and finally appears in the tail only at metamorphic climax. Finally, our analysis reveals that the TH-induced down-regulated gene expression program during metamorphosis is very different from the previously described up-regulated program which involves multiple cell types and several waves of gene expression changes. The down-regulated program only consists of the repression of a small number of genes which are expressed in larval cells preprogrammed to die during the larval to adult transition at metamorphosis.

Obesity is a major cause of non-alcoholic fatty liver disease (NAFLD). NAFLD is an epidemic affecting nearly 34% of the adult population in the US. As a chronic inflammatory disease, NAFLD influences the immune system by dysregulating T-cell activity. Remedies for the adverse effects on the immune system are urgently needed. We studied Theaphenon E (TE), a standardized formulation of green tea extract, on the adverse effects of NAFLD in C57BL/6J mice fed a high fat diet (HFD). Mice received HFD, low fat diet (LFD) or HFD+2% TE for 35 weeks. Hepatic lipid accumulation, cell proliferation, apoptosis and CD4+T lymphocytes were measured throughout the bioassay. The hepatic composition of fatty acids was determined. The effects of epigallocatechin gallate (EGCG) metabolites on lipid accumulation in mouse and primary human liver cells were studied. Unlike mice receiving HFD, mice on HFD+2% TE maintained normal liver to body weight ratios with low levels of alanine and aspartate aminotransferase (ALT and AST). Hepatic lipid accumulation was observed in HFD mice, accompanied by increased proliferation, reduced apoptosis and loss of CD4+ T lymphocytes. TE significantly inhibited lipid accumulation, decreased proliferation, induced apoptosis and increased CD4+ T cell survival in HFD mice. It was found that the EGCG metabolite EGC-M3 reduced lipid accumulation in mouse and human hepatocytes. Linoleic acid showed the largest increase (2.5-fold) in livers of mice on a HFD and this increase was significantly suppressed by TE. Livers of HFD-fed mice showed lipid accumulation, increased proliferation, reduced apoptosis, elevated linoleic acid and loss of CD4+ T cells. TE effectively ameliorated all of these adverse effects. [ABSTRACT FROM AUTHOR]

Thyroid hormone (TH) induces dramatic skeletal and tissue remodeling of the anuran head and body at metamorphosis. The expression pattern of TH up-regulated genes has been correlated with tissues that either grow or resorb at metamorphosis. Whereas the expression of the thyroid hormone receptors in Xenopus laevis tadpoles is ubiquitous, the locations where many of the TH up-regulated genes are activated fall into distinct classes. Genes in the early response class are expressed predominantly in cartilage and brain regions undergoing cell proliferation and at a higher level in the remodeling and growing body than in the resorbing tail. In contrast, expression of genes in the delayed response class is highest in resorbing tissues and higher in the tail than in the body within the subepidermal fibroblast layer, further indicating that this single cell layer is involved in tissue resorption. The expression boundary of delayed response class genes in the subepidermal fibroblasts in the body correlates with epidermal lamella invasion and subsequent adult skin differentiation. Differences in the expression patterns of stromelysin-3 and the delayed response proteinases in the head delineate separate programs of tissue resorption, one for the loss of epithelial structures, and one for the loss of cartilages. Expression of the type III deiodinase is up-regulated in growing tissues nearing completion of their metamorphic changes, suggesting a role for the deiodinase in modulating the influence of TH on these tissues. Key Words: metamorphosis; thyroid hormone; Xenopus laevis.

Expression of genes up-regulated by thyroid hormone (TH) during amphibian tail resorption was localized by in situ hybridization. The constitutive thyroid hormone receptor (TR[Alpha]) and its heterodimeric partners (RXR[Alpha] and RXR[Beta]) are expressed ubiquitously in the resorbing tail. A group of early response genes, including those encoding transcription factors, are expressed at greatest levels within tissues whose cells attempt to grow and differentiate in the tail, but eventually succumb to the resorption program. The TH-inducible TR isoform, TR[Beta], is expressed ubiquitously in the tail, but especially high in fibroblasts. Similarly, a group of delayed response genes including two proteolytic enzymes that appear to execute the tail resorption program, is expressed specifically in fibroblasts that line and surround the notochord and lie beneath the epidermal lamella (subepidermal fibroblasts). During active tail resorption these fibroblasts invade their neighboring epidermal and notochord lamellae as part of the resorption process. Expression analysis implicates the single layer of invasive subepidermal fibroblasts as crucial in tail resorption. Stromelysin-3 is up-regulated by TH with early kinetics, and is expressed most actively in fibroblasts within the tail fins. None of the proteases are expressed in the tadpole epidermis, which will be replaced entirely during metamorphosis. While very few TH response genes are expressed in tadpole muscle, many are activated in fibroblasts that surround muscle and could induce muscle cell death by proteolysis of the extracellular matrix. These distinct localization patterns suggest that the common fate of all cell types within the tail is the result of multiple genetic programs. Key Words: metamorphosis; thyroid hormone; Xenopus laevis.

The acrolein derived cyclic 1,N 2 -propanodeoxyguanosine adduct (Acr-dG), formed primarily from ω-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) under oxidative conditions, while proven to be mutagenic, is potentially involved in DHA-induced apoptosis. The latter may contribute to the chemopreventive effects of DHA. Previous studies have shown that the levels of Acr-dG are correlated with apoptosis induction in HT29 cells treated with DHA. Because Acr-dG is shown to be repaired by the nucleotide excision repair (NER) pathway, to further investigate the role of Acr-dG in apoptosis, in this study, NER-deficient XPA and its isogenic NER-proficient XAN1 cells were treated with DHA. The Acr-dG levels and apoptosis were sharply increased in XPA cells, but not in XAN1 cells when treated with 125 μM of DHA. Because DHA can induce formation of various DNA damage, to specifically investigate the role of Acr-dG in apoptosis induction, we treated XPA knockdown HCT116 + ch3 cells with acrolein. The levels of both Acr-dG and apoptosis induction increased significantly in the XPA knockdown cells. These results clearly demonstrate that NER deficiency induces higher levels of Acr-dG in cells treated with DHA or acrolein and sensitizes cells to undergo apoptosis in a correlative manner. Collectively, these results support that Acr-dG, a ubiquitously formed mutagenic oxidative DNA adduct, plays a role in DHA-induced apoptosis and suggest that it could serve as a biomarker for the cancer preventive effects of DHA. [ABSTRACT FROM AUTHOR]

Objective: Improvements to bladder cancer risk stratification guidelines are needed to better tailor post-operative surveillance and adjuvant therapy to individual patients. We previously identified STAG2 as a commonly mutated tumor suppressor gene in bladder cancer and an independent predictor of progression in NMIBC. Here we test the value of combining STAG2 immunostaining with other risk stratification biomarkers in NMIBC, and as an individual biomarker in MIBC.Materials and Methods: STAG2 immunohistochemistry was performed on a progressor-enriched cohort of tumors from 297 patients with NMIBC, and on tumors from 406 patients with MIBC from Aarhus University Hospital in Denmark. Survival analysis was performed using Kaplan-Meier survival analysis, the log rank test, and Cox proportional hazards models.Results: STAG2-negative low-grade NMIBC tumors were 2.5 times less likely to progress to muscle invasion than STAG2-positive low-grade NMIBC tumors (Log-rank test, P = 0.008). In a composite group of patients with AUA intermediate and high-risk NMIBC tumors, STAG2-negative tumors were less likely to progress (Log-rank test, P = 0.02). In contrast to NMIBC, we show that STAG2 is not useful as a prognostic biomarker in MIBC.Conclusions: STAG2 immunostaining can be used to subdivide low-grade NMIBC tumors into two groups with substantially different risks of disease progression. Furthermore, STAG2 immunostaining may be useful to enhance NMIBC risk stratification guidelines, though larger cohorts are needed to solidify this conclusion in individual risk groups. STAG2 is not useful as a biomarker in MIBC. Further study of the use of STAG2 immunostaining as a biomarker for predicting the clinical behavior in NMIBC is warranted. [ABSTRACT FROM AUTHOR]