title: Ell3 stabilizes p53 following CDDP treatment via its effects on ubiquitin-dependent and -independent proteasomal degradation pathways in breast cancer cells.
abstract: The tumor suppressor protein p53 is unstable in quiescent cells and undergoes proteosomal degradation. Under conditions of cellular stress, p53 is rapidly stabilized by post-translational modification, thereby escaping degradation and translocating to the nucleus where it activates genes related to cell cycle arrest or apoptosis. Here, we report that the transcription elongation factor Ell3 sensitizes luminal type-cancer cell line, MCF7, which have wild-type p53, to the chemotherapeutic agent cis-diamminedichloroplatinum(II) (CDDP) by stabilizing p53. Overexpression of Ell3 in MCF7 cells suppressed the MDM2-mediated ubiquitin-dependent degradation pathway. In addition, Ell3 promoted binding of p53 to NADH quinone oxidoreductase 1, which is linked to the ubiquitin-independent degradation of p53. We found that Ell3 activates interleukin-20 (IL20) expression, which is linked to the ERK1/2 signaling pathway. Chemical inhibition of ERK1/2 signaling or molecular suppression of IL20 revealed that the ERK1/2 signaling pathway and IL20 are the main causes of p53 stabilization in Ell3-overexpressing MCF7 cells. These findings suggest that the ERK1/2 pathway can be targeted in the rational development of therapies to induce chemosensitization of breast cancer cells.
authors.affiliation: Department of Biomedical Science, College of Life Science and CHA Stem Cell Institute, CHA University, Seoul, Korea.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Ahn
authors.affiliation: Department of Biomedical Science, College of Life Science and CHA Stem Cell Institute, CHA University, Seoul, Korea.
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Graduate School of Biomedical Science, CHA University, Seoul, Korea.
authors.forename: Kyung-Won
authors.initials: KW
authors.lastname: Shin
authors.affiliation: Department of Biomedical Science, College of Life Science and CHA Stem Cell Institute, CHA University, Seoul, Korea.
authors.forename: Kee-Hwan
authors.initials: KH
authors.lastname: Lim
authors.affiliation: Department of Biomedical Science, College of Life Science and CHA Stem Cell Institute, CHA University, Seoul, Korea.
authors.forename: Jin-Ock
authors.initials: JO
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science, College of Life Science and CHA Stem Cell Institute, CHA University, Seoul, Korea.
authors.forename: Je-Yong
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Biomedical Science, College of Life Science and CHA Stem Cell Institute, CHA University, Seoul, Korea.
authors.forename: Jiewan
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science, College of Life Science and CHA Stem Cell Institute, CHA University, Seoul, Korea.
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Biomedical Science, College of Life Science and CHA Cancer Institute, CHA University, Seoul, Korea.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Yang
authors.affiliation: Department of Biomedical Science, College of Life Science and CHA Stem Cell Institute, CHA University, Seoul, Korea.
authors.forename: Kwang-Hyun
authors.initials: KH
authors.lastname: Baek
authors.affiliation: Department of Biomedical Science, College of Life Science and CHA Stem Cell Institute, CHA University, Seoul, Korea.
authors.forename: Jeong-Jae
authors.initials: JJ
authors.lastname: Ko
authors.affiliation: Department of Biomedical Science, College of Life Science and CHA Stem Cell Institute, CHA University, Seoul, Korea.
authors.forename: Kyung-Soon
authors.initials: KS
authors.lastname: Park
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D055550:Protein Stability; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D035602:Transcriptional Elongation Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C415468:ELL3 protein, human; D007378:Interleukins; C495901:TP53 protein, human; D035602:Transcriptional Elongation Factors; D016159:Tumor Suppressor Protein p53; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex; D002945:Cisplatin; C422042:interleukin 20
keywords: Ell3; NAD(P)H quinone oxidoreductase 1 (NQO1); cis-diamminedichloroplatinum(II) (CDDP); interleukin-20 (IL20); p53