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  • 1
    Publication Date: 2000-08-26
    Description: Chromosomal translocations that encode fusion oncoproteins have been observed consistently in leukemias/lymphomas and sarcomas but not in carcinomas, the most common human cancers. Here, we report that t(2;3)(q13;p25), a translocation identified in a subset of human thyroid follicular carcinomas, results in fusion of the DNA binding domains of the thyroid transcription factor PAX8 to domains A to F of the peroxisome proliferator-activated receptor (PPAR) gamma1. PAX8-PPARgamma1 mRNA and protein were detected in 5 of 8 thyroid follicular carcinomas but not in 20 follicular adenomas, 10 papillary carcinomas, or 10 multinodular hyperplasias. PAX8-PPARgamma1 inhibited thiazolidinedione-induced transactivation by PPARgamma1 in a dominant negative manner. The experiments demonstrate an oncogenic role for PPARgamma and suggest that PAX8-PPARgamma1 may be useful in the diagnosis and treatment of thyroid carcinoma.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kroll, T G -- Sarraf, P -- Pecciarini, L -- Chen, C J -- Mueller, E -- Spiegelman, B M -- Fletcher, J A -- CA75425/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2000 Aug 25;289(5483):1357-60.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. tkroll@rics.bwh.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10958784" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma, Follicular/*genetics/metabolism ; Adenoma/genetics/metabolism ; Adult ; Aged ; Carcinoma, Papillary/genetics/metabolism ; Cell Line ; Cell Nucleus/metabolism ; Child ; DNA-Binding Proteins/chemistry/genetics/pharmacology/*physiology ; Humans ; Middle Aged ; *Nuclear Proteins ; Oncogene Proteins, Fusion/chemistry/genetics/*physiology ; Paired Box Transcription Factors ; Receptors, Cytoplasmic and Nuclear/chemistry/genetics/*physiology ; Response Elements ; Thiazoles/pharmacology ; *Thiazolidinediones ; Thyroid Neoplasms/*genetics/metabolism ; Trans-Activators/chemistry/genetics/pharmacology/*physiology ; Transcription Factors/chemistry/genetics/pharmacology/*physiology ; Transcription, Genetic ; Transcriptional Activation ; Translocation, Genetic
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-10-12
    Description: Lifeguard (LFG) is an inhibitor of Fas-mediated cell death and is highly expressed in the cerebellum. We investigated the biological role of LFG in the cerebellum in vivo, using mice with reduced LFG expression generated by shRNA lentiviral transgenesis (shLFG mice) as well as LFG null mice. We found that LFG plays a role in cerebellar development by affecting cerebellar size, internal granular layer (IGL) thickness, and Purkinje cell (PC) development. All these features are more severe in early developmental stages and show substantial recovery overtime, providing a remarkable example of cerebellar plasticity. In adult mice, LFG plays a role in PC maintenance shown by reduced cellular density and abnormal morphology with increased active caspase 8 and caspase 3 immunostaining in shLFG and knockout (KO) PCs. We studied the mechanism of action of LFG as an inhibitor of the Fas pathway and provided evidence of the neuroprotective role of LFG in cerebellar granule neurons (CGNs) and PCs in an organotypic cerebellar culture system. Biochemical analysis of the Fas pathway revealed that LFG inhibits Fas-mediated cell death by interfering with caspase 8 activation. This result is supported by the increased number of active caspase 8-positive PCs in adult mice lacking LFG. These data demonstrate that LFG is required for proper development and survival of granular and Purkinje cells and suggest LFG may play a role in cerebellar disorders.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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