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Open AccessArticle

ALDH1A1 Deficiency in Gorlin Syndrome Suggests a Central Role for Retinoic Acid and ATM Deficits in Radiation Carcinogenesis

Systems Toxicology and Exposure Science, Pacific Northwest National Laboratory, Richland, WA 99352, USA
Faculté de Médicine, 2ème étage, CNRS UMR 6267—INSERM U998—UNSA, Nice 06107 Cedex 2, France
College of Osteopathic Medicine of the Pacific-Northwest, Western University of Health Sciences, Lebanon, OR 97355, USA
Author to whom correspondence should be addressed.
Proteomes 2014, 2(3), 451-467;
Received: 9 April 2014 / Revised: 11 August 2014 / Accepted: 1 September 2014 / Published: 11 September 2014
(This article belongs to the Special Issue Radiation Proteomics)
PDF [765 KB, uploaded 11 September 2014]


We hypothesize that aldehyde dehydrogenase 1A1 (ALDH1A1) deficiency will result in impaired ataxia-telangiectasia mutated (ATM) activation in a retinoic acid-sensitive fashion. Data supporting this hypothesis include (1) reduced ATM activation in irradiated primary dermal fibroblasts from ALDH1A1-deficient Gorlin syndrome patients (GDFs), relative to ALDH1A1-positive normal human dermal fibroblasts (NHDFs) and (2) increased ATM activation by X-radiation in GDFs pretreated with retinoic acid, however, the impact of donor variability on ATM activation in fibroblasts was not assessed and is a prudent consideration in future studies. Clonogenic survival of irradiated cells showed differential responses to retinoic acid as a function of treatment time. Long-term (5 Day) retinoic acid treatment functioned as a radiosensitizer and was associated with downregulation of ATM protein levels. Short-term (7 h) retinoic acid treatment showed a trend toward increased survival of irradiated cells and did not downregulate ATM protein levels. Using a newly developed IncubATR technology, which defines changes in bulk chemical bond patterns in live cells, we can discriminate between the NHDF and GDF phenotypes, but treatment of GDFs with retinoic acid does not induce reversion of bulk chemical bond patterns associated with GDFs toward the NHDF phenotype. Collectively, our preliminary investigation of the Gorlin phenotype has identified deficient ALDH1A1 expression associated with deficient ATM activation as a possible susceptibility factor that is consistent with the high incidence of spontaneous and radiation-induced carcinogenesis in these patients. The IncubATR technology exhibits sufficient sensitivity to detect phenotypic differences in live cells that may be relevant to radiation health effects. View Full-Text
Keywords: Gorlin; ATM; carcinogenesis; retinoic acid Gorlin; ATM; carcinogenesis; retinoic acid

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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Weber, T.J.; Magnaldo, T.; Xiong, Y. ALDH1A1 Deficiency in Gorlin Syndrome Suggests a Central Role for Retinoic Acid and ATM Deficits in Radiation Carcinogenesis. Proteomes 2014, 2, 451-467.

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