Document Detail


DNA damage recognition via activated ATM and p53 pathway in nonproliferating human prostate tissue.
MedLine Citation:
PMID:  20978201     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
DNA damage response (DDR) pathways have been extensively studied in cancer cell lines and mouse models, but little is known about how DNA damage is recognized by different cell types in nonmalignant, slowly replicating human tissues. Here, we assess, using ex vivo cultures of human prostate tissue, DDR caused by cytotoxic drugs (camptothecin, doxorubicin, etoposide, and cisplatin) and ionizing radiation (IR) in the context of normal tissue architecture. Using specific markers for basal and luminal epithelial cells, we determine and quantify cell compartment-specific damage recognition. IR, doxorubicin, and etoposide induced the phosphorylation of H2A.X on Ser(139) (γH2AX) and DNA damage foci formation. Surprisingly, luminal epithelial cells lack the prominent γH2AX response after IR when compared with basal cells, although ATM phosphorylation on Ser(1981) and 53BP1 foci were clearly detectable in both cell types. The attenuated γH2AX response seems to result from low levels of total H2A.X in the luminal cells. Marked increase in p53, a downstream target of the activated ATM pathway, was detected only in response to camptothecin and doxorubicin. These findings emphasize the diversity of pathways activated by DNA damage in slowly replicating tissues and reveal an unexpected deviation in the prostate luminal compartment that may be relevant in prostate tumorigenesis. Detailed mapping of tissue and cell type differences in DDR will provide an outlook of relevant responses to therapeutic strategies.
Authors:
Sari Jäämaa; Taija M Af Hällström; Anna Sankila; Ville Rantanen; Hannu Koistinen; Ulf-Håkan Stenman; Zhewei Zhang; Zhiming Yang; Angelo M De Marzo; Kimmo Taari; Mirja Ruutu; Leif C Andersson; Marikki Laiho
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-26
Journal Detail:
Title:  Cancer research     Volume:  70     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-02     Completed Date:  2010-12-21     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8630-41     Citation Subset:  IM    
Copyright Information:
©2010 AACR.
Affiliation:
Biomedicum Helsinki and Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology
Cell Cycle Proteins / metabolism*
DNA Damage / physiology*,  radiation effects
DNA-Binding Proteins / metabolism*
Histones / metabolism
Humans
Immunoenzyme Techniques
Intracellular Signaling Peptides and Proteins
Male
Phosphorylation / radiation effects
Prostate / metabolism*,  pathology*
Protein-Serine-Threonine Kinases / metabolism*
Radiation, Ionizing
Signal Transduction*
Tumor Suppressor Protein p53 / metabolism*
Tumor Suppressor Proteins / metabolism*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/H2AFX protein, human; 0/Histones; 0/Intracellular Signaling Peptides and Proteins; 0/TP53 protein, human; 0/TP53BP1 protein, human; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein

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