Gene interactions and pathways from curated databases and text-mining
Cell Res 2010, PMID: 20368736

BNIP3 is essential for mediating 6-thioguanine- and 5-fluorouracil-induced autophagy following DNA mismatch repair processing.

Zeng, Xuehuo; Kinsella, Timothy J

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.

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Text Mining Data

mTOR ⊣ p53: " 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 "

BNIP3 → mTOR: " 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 "

Manually curated Databases

No curated data.