title: Tumor suppressor p53 plays a key role in induction of both tristetraprolin and let-7 in human cancer cells.
abstract: Tristetraprolin (TTP) and let-7 microRNA exhibit suppressive effects on cell growth through down-regulation of oncogenes. Both TTP and let-7 are often repressed in human cancers, thereby promoting oncogenesis by derepressing their target genes. However, the precise mechanism of this repression is unknown. We here demonstrate that p53 stimulated by the DNA-damaging agent doxorubicin (DOX) induced the expression of TTP in cancer cells. TTP in turn increased let-7 levels through down-regulation of Lin28a. Correspondingly, cancer cells with mutations or inhibition of p53 failed to induce the expression of both TTP and let-7 on treatment with DOX. Down-regulation of TTP by small interfering RNAs attenuated the inhibitory effect of DOX on let-7 expression and cell growth. Therefore, TTP provides an important link between p53 activation induced by DNA damage and let-7 biogenesis. These novel findings provide a mechanism for the widespread decrease in TTP and let-7 and chemoresistance observed in human cancers.
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Nal Ae
authors.initials: NA
authors.lastname: Yoon
authors.forename: Won Hyeok
authors.initials: WH
authors.lastname: Lee
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Min
authors.forename: Byung Kyun
authors.initials: BK
authors.lastname: Ko
authors.forename: Byung Ju
authors.initials: BJ
authors.lastname: Lee
authors.forename: Aran
authors.initials: A
authors.lastname: Lee
authors.forename: Hee Jeong
authors.initials: HJ
authors.lastname: Cha
authors.forename: Wha Ja
authors.initials: WJ
authors.lastname: Cho
authors.forename: Jeong Woo
authors.initials: JW
authors.lastname: Park
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis*; D009154:Mutation; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins / Q000378:metabolism; D051816:Tristetraprolin / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: C000715187:Lin28A protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D051816:Tristetraprolin; D016159:Tumor Suppressor Protein p53; C487931:mirnlet7 microRNA, human; D004317:Doxorubicin