Source:http://linkedlifedata.com/resource/pubmed/id/20368736
Switch to
Predicate | Object |
---|---|
rdf:type | |
lifeskim:mentions | |
pubmed:issue |
6
|
pubmed:dateCreated |
2010-6-3
|
pubmed:abstractText |
DNA mismatch repair (MMR) processes the chemically induced mispairs following treatment with clinically important nucleoside analogs such as 6-thioguanine (6-TG) and 5-fluorouracil (5-FU). MMR processing of these drugs has been implicated in activation of a prolonged G2/M cell cycle arrest for repair and later induction of apoptosis and/or autophagy for irreparable DNA damage. In this study, we investigated the role of Bcl2 and adenovirus E1B Nineteen-kilodalton Interacting Protein (BNIP3) in the activation of autophagy, and the temporal relationship between a G2/M cell cycle arrest and the activation of BNIP3-mediated autophagy following MMR processing of 6-TG and 5-FU. We found that BNIP3 protein levels are upregulated in a MLH1 (MMR(+))-dependent manner following 6-TG and 5-FU treatment. Subsequent small-interfering RNA (siRNA)-mediated BNIP3 knockdown abrogates 6-TG-induced autophagy. We also found that p53 knockdown or inhibition of mTOR activity by rapamycin cotreatment impairs 6-TG- and 5-FU-induced upregulation of BNIP3 protein levels and autophagy. Furthermore, suppression of Checkpoint kinase 1 (Chk1) expression with a subsequent reduction in 6-TG-induced G2/M cell cycle arrest by Chk1 siRNA promotes the extent of 6-TG-induced autophagy. These findings suggest that BNIP3 mediates 6-TG- and 5-FU-induced autophagy in a p53- and mTOR-dependent manner. Additionally, the duration of Chk1-activated G2/M cell cycle arrest determines the level of autophagy following MMR processing of these nucleoside analogs.
|
pubmed:grant | |
pubmed:language |
eng
|
pubmed:journal | |
pubmed:citationSubset |
IM
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antimetabolites, Antineoplastic,
http://linkedlifedata.com/resource/pubmed/chemical/BNIP3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Fluorouracil,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/TOR Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Thioguanine,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Protein p53,
http://linkedlifedata.com/resource/pubmed/chemical/bcl-Associated Death Protein
|
pubmed:status |
MEDLINE
|
pubmed:month |
Jun
|
pubmed:issn |
1748-7838
|
pubmed:author | |
pubmed:issnType |
Electronic
|
pubmed:volume |
20
|
pubmed:owner |
NLM
|
pubmed:authorsComplete |
Y
|
pubmed:pagination |
665-75
|
pubmed:meshHeading |
pubmed-meshheading:20368736-Antimetabolites, Antineoplastic,
pubmed-meshheading:20368736-Apoptosis,
pubmed-meshheading:20368736-Autophagy,
pubmed-meshheading:20368736-DNA Damage,
pubmed-meshheading:20368736-DNA Mismatch Repair,
pubmed-meshheading:20368736-Fluorouracil,
pubmed-meshheading:20368736-HCT116 Cells,
pubmed-meshheading:20368736-Humans,
pubmed-meshheading:20368736-Membrane Proteins,
pubmed-meshheading:20368736-Proto-Oncogene Proteins,
pubmed-meshheading:20368736-TOR Serine-Threonine Kinases,
pubmed-meshheading:20368736-Thioguanine,
pubmed-meshheading:20368736-Tumor Suppressor Protein p53,
pubmed-meshheading:20368736-bcl-Associated Death Protein
|
pubmed:year |
2010
|
pubmed:articleTitle |
BNIP3 is essential for mediating 6-thioguanine- and 5-fluorouracil-induced autophagy following DNA mismatch repair processing.
|
pubmed:affiliation |
Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH 44106, USA.
|
pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
|