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

Abstract

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 the pathways/networks that contribute to pathophysiological outcomes. Here we interrogate primary dermal fibroblasts isolated from Gorlin syndrome patients (GDFs), who display a pronounced inducible tumorigenic response to radiation, in comparison to normal human dermal fibroblasts (NHDFs). Our approach exploits newly developed thiol reactive probes to define changes in protein thiol profiles in live cell studies, which minimizes artifacts associated with cell lysis. Redox probes revealed deficient expression of an apparent 55 kDa protein thiol in GDFs from independent Gorlin syndrome patients, compared with NHDFs. Proteomics tentatively identified this protein as aldehyde dehydrogenase 1A1 (ALDH1A1), a key enzyme regulating retinoic acid synthesis, and ALDH1A1 protein deficiency in GDFs was confirmed by Western blot. A number of additional protein thiol differences in GDFs were identified, including radiation responsive annexin family members and lamin A/C. Collectively, candidates identified in our study have plausible implications for radiation health effects and cancer susceptibility.

Electrochemical Biosensor Composed of Silver Ion‐Mediated dsDNA on Au‐Encapsulated Bi2Se3 Nanoparticles for the Detection of H2O2 Released from Breast Cancer Cells

“…The regression equation was i pc = 0.022 C (μ m ) − 2.15e −5 ( R 2 = 0.991) and the detection limit was measured 0.25 × 10 −6 m . Although, the Pierce showed a wider dynamic range, the importance of the sensitivity of the H 2 O 2 biosensor should not be neglected; for instance, the low concentrations of hydrogen peroxide can induce DNA lesions, cause many oxidative stresses, and affect viability of dermal fibroblasts (at the concentration of 16–32 × 10 −9 m ) . As a result, having an accurate linear dynamic range in the very low concentrations range would be demanding.…”

Nevoid Basal Cell Carcinoma Syndrome: Report from the Zurich Nevoid Basal Cell Carcinoma Syndrome Cohort

“…Due to the patients' high sensitivity to radiation, no additional radiographs were made [14]. Additional MRI examinations could not be realized due to the costs.…”

Dinitrogenase-Driven Photobiological Hydrogen Production Combats Oxidative Stress in Cyanothece sp. Strain ATCC 51142

“…Characterizing Cyanothece sp. 51142 protein redox dynamics during H 2 production provided a snapshot into the cells' response to their environment and active reductant allocation (11)(12)(13). This was achieved by a chemoproteomic approach utilized to characterize in vivo redox dynamics with cysteine thiol redox-reactive chemical probes (IM-RPs) (Fig.…”

“…The IM-RPs include N-ethylmaleimide (Mal-RP) and iodoacetamide (IAM-RP) derivatives that cross cell membranes and covalently bind to reduced cysteine thiols directly in live cells, thereby yielding readout of protein redox dynamics under the physiological conditions of the experiment. Probe-labeled proteins are then characterized and quantified by LC-MS-based proteomic analyses (11)(12)(13). IM-RPs were applied to live cells over the time course at points corresponding to differing H 2 production inflections, and a tandem cleavage technique to characterize cysteine sites of probe labeling was utilized to gain insight into redoxsensitive thiols for labeled proteins (11,29).…”

“…51142 cells held under an Ar atmosphere were transitioned from N-limited chemostat growth to a N-depleted state and incubated with or without CO 2 . The cell dynamics were interrogated via a chemical probe-based chemoproteomic technique (11)(12)(13) to quantify which specific protein redox dynamics in vivo were correlated with H 2 production. Along with identifying the pro-teins that were reduced and probe labeled throughout each time course, we also used tandem protein cleavage techniques to identify the cysteine(s) responsible for conferring redox reactivity.…”