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Title: Deficient expression of aldehyde dehydrogenase 1A1 is consistent with increased sensitivity of Gorlin syndrome patients to radiation carcinogenesis

Human phenotypes that are highly susceptible to radiation carcinogenesis have been identified. Sensitive phenotypes often display robust regulation of molecular features that modify biological response, which can facilitate identification of relevant pathways/networks. Here we interrogate primary dermal fibroblasts isolated from Gorlin syndrome patients (GDFs), who display a pronounced tumorigenic response to radiation, in comparison to normal human dermal fibroblasts (NHDFs). Our approach exploits newly developed thiol-reactive probes with a flexible click chemistry functional group to define changes in protein thiol profiles in live cell studies, which minimizes artifacts associated with cell lysis. We observe qualitative differences in protein thiol profiles by SDS-PAGE analysis when detection by iodoacetamide vs maleimide probe chemistries are compared, and pretreatment of cells with hydrogen peroxide eliminates detection of the majority of SDS-PAGE bands. Redox probes revealed deficient expression of an apparent 55 kDa protein thiol in GDFs from independent donors, compared with NHDFs. Proteomics tentatively identified this protein as aldehyde dehydrogenase 1A1 (ALDH1A1), a key enzyme regulating retinoic acid synthesis, and this deficiency was confirmed by Western blot. Redox probes revealed additional protein thiol differences between GDFs and NHDFs, including radiation responsive annexin family members. Our results indicate a multifactorial basis for the unusual sensitivitymore » of Gorlin syndrome to radiation carcinogenesis, and the pathways identified have plausible implications for radiation health effects.« less
 [1] ;  [2] ;  [3] ;  [1] ;  [1] ;  [1] ;  [4] ;  [5]
  1. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Omic Biological Applications
  2. Centre national de la recherche scientifique (CNRS), Nice (France). Faculte de Medicine
  3. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Systems Toxicology Group
  4. Centre national de la recherche scientifique (CNRS), Nice (France). Inst. for Research on Cancer and Aging
  5. Systems Toxicology Group, Pacific Northwest National Laboratory, Richland Washington
Publication Date:
Report Number(s):
Journal ID: ISSN 0899-1987; 47292; KP1602020
Grant/Contract Number:
AC05-76RL01830; 8P41GM103493-10; ET9-551; SFI201212055859
Accepted Manuscript
Journal Name:
Molecular Carcinogenesis
Additional Journal Information:
Journal Volume: 54; Journal Issue: 6; Journal ID: ISSN 0899-1987
Research Org:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
62 RADIOLOGY AND NUCLEAR MEDICINE; Gorlin syndrome; radiation; retinoic acid; carcinogenesis; protein thiol; Environmental Molecular Sciences Laboratory
OSTI Identifier: