| 1. |
- Pasche, Boris, et al.
(författare)
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Somatic acquisition and signaling of TGFBR1*6A in cancer
- 2005
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 294:13, s. 1634-1646
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Tidskriftsartikel (refereegranskat)abstract
- Context: TGFBR1*6A is a common polymorphism of the type I transforming growth factor 0 receptor (TGFBR1). Epidemiological studies suggest that TGFBR1*6A may act as a tumor susceptibility allele. How TGFBR1*6A contributes to cancer development is largely unknown.. Objectives: To determine whether TGFBR1*6A is somatically acquired by primary tumors and metastases during cancer development and whether the 3-amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells. Design, Setting, and Patients: Tumor And germline tissues from 531 patients with a diagnosis of head and neck, colorectal, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004, In vitro translation assays, MCF-7 breast cancer cells stably transfected with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1 colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A. Main Outcome Measures: TGFBR1*6A somatic acquisition in cancer. Determination of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination of TGF-beta-dependent cell proliferation. Results: TGFBR1*6A was somatically acquired in 13 of 44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the 104 patients with breast cancer. TGFBR1*6A somatic acquisition is not associated with loss of heterozygosity, microsatellite instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF-beta growth inhibitory signals into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1 colorectal cancer cells. Conclusions: TGFBR1*6A is somatically acquired in 29.5% of liver metastases from colorectal cancer and may bestow cancer cells with a growth advantage in the presence of TGF-beta. The functional consequences of this conversion appear to be mediated by the TGFBR1*6A signal sequence rather than by the mature receptor. The results highlight a new facet of TGF-beta signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer.
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| 2. |
- Jönsson, Henrik, et al.
(författare)
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Modeling the organization of the WUSCHEL expression domain in the shoot apical meristem
- 2005
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1460-2059. ; 21:Suppl 1, s. 232-240
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Tidskriftsartikel (refereegranskat)abstract
- Motivation: The above-ground tissues of higher plants are generated from a small region of cells situated at the plant apex called the shoot apical meristem. An important genetic control circuit modulating the size of the Arabidopsis thaliana meristem is a feed-back network between the CLAVATA3 and WUSCHEL genes. Although the expression patterns for these genes do not overlap, WUSCHEL activity is both necessary and sufficient (when expressed ectopically) for the induction of CLAVATA3 expression. However, upregulation of CLAVATA3 in conjunction with the receptor kinase CLAVATA1 results in the downregulation of WUSCHEL. Despite much work, experimental data for this network are incomplete and additional hypotheses are needed to explain the spatial locations and dynamics of these expression domains. Predictive mathematical models describing the system should provide a useful tool for investigating and discriminating among possible hypotheses, by determining which hypotheses best explain observed gene expression dynamics. Results: We are developing a method using in vivo live confocal microscopy to capture quantitative gene expression data and create templates for computational models. We present two models accounting for the organization of the WUSCHEL expression domain. Our preferred model uses a reaction-diffusion mechanism in which an activator induces WUSCHEL expression. This model is able to organize the WUSCHEL expression domain. In addition, the model predicts the dynamical reorganization seen in experiments where cells, including the WUSCHEL domain, are ablated, and it also predicts the spatial expansion of the WUSCHEL domain resulting from removal of the CLAVATA3 signal.
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| 3. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
- 2008
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Ingår i: Autophagy. - : Landes Bioscience. - 1554-8627 .- 1554-8635. ; 4:2, s. 151-175
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Forskningsöversikt (refereegranskat)abstract
- Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.2,3 There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
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