title: Differential responses of neuronal and spermatogenic cells to the doppel cytotoxicity.
abstract: Although structurally and biochemically similar to the cellular prion (PrP(C)), doppel (Dpl) is unique in its biological functions. There are no reports about any neurodegenerative diseases induced by Dpl. However the artificial expression of Dpl in the PrP-deficient mouse brain causes ataxia with Purkinje cell death. Abundant Dpl proteins have been found in testis and depletion of the Dpl gene (Prnd) causes male infertility. Therefore, we hypothesize different regulations of Prnd in the nerve and male productive systems. In this study, by electrophoretic mobility shift assays we have determined that two different sets of transcription factors are involved in regulation of the Prnd promoter in mouse neuronal N2a and GC-1 spermatogenic (spg) cells, i.e., upstream stimulatory factors (USF) in both cells, Brn-3 and Sp1 in GC-1 spg cells, and Sp3 in N2a cells, leading to the expression of Dpl in GC-1 spg but not in N2a cells. We have further defined that, in N2a cells, Dpl induces oxidative stress and apoptosis, which stimulate ataxia-telangiectasia mutated (ATM)-modulating bindings of transcription factors, p53 and p21, to Prnp promoter, resulting the PrP(C) elevation for counteraction of the Dpl cytotoxicity; in contrast, in GC-1 spg cells, phosphorylation of p21 and N-terminal truncated PrP may play roles in the control of Dpl-induced apoptosis, which may benefit the physiological function of Dpl in the male reproduction system.
authors: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Wenzhou Medical University, Wenzhou, China ; Department of Microbiology, Fourth Military Medical University, Xi'an, China ; Department of Neurology, University of Chicago, Chicago, Illinois, United States of America.
authors: Kefeng
authors: K
authors: Qin
authors: Tianbing
authors: T
authors: Ding
authors: Yi
authors: Y
authors: Xiao
authors: Wenyu
authors: W
authors: Ma
authors: Zhen
authors: Z
authors: Wang
authors: Jimin
authors: J
authors: Gao
authors: Lili
authors: L
authors: Zhao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018621:PrPC Proteins / Q000096:biosynthesis / Q000235:genetics; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D013091:Spermatogenesis / Q000502:physiology*; D013094:Spermatozoa / Q000166:cytology / Q000378:metabolism*; D050819:Transcription Factor Brn-3A / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D058851:GPI-Linked Proteins; C494189:Pou4f1 protein, mouse; D018621:PrPC Proteins; D011328:Prions; C122036:Prnd protein, mouse; D016329:Sp1 Transcription Factor; D050819:Transcription Factor Brn-3A; D016159:Tumor Suppressor Protein p53