title: ASK1/JNK-mediated TAp63 activation controls the cell survival signal of baicalein-treated EBV-transformed B cells.
abstract: Transcriptionally active p63 (TAp63) promotes cell cycle arrest, senescence, and apoptosis in several cancer cells. Migration inhibitory factor (MIF)/CD74 regulates B-cell survival through nuclear factor (NF)-κB-dependent TAp63 expression. In this study, we investigated how the level of TAp63 expression influences the induction of apoptosis in baicalein-treated EBV-transformed B cells. Baicalein induced the expression of TAp63 and apoptosis signal-regulating kinase 1 (ASK1), as well as cytotoxicity, by disrupting the mitochondrial membrane and inhibiting the activation of phosphoinositide 3-kinase (PI3K)/Akt and NF-κB. Genetic knockdown of TAp63 or ASK1 by small interfering RNA resulted in protection from apoptosis accompanied by the recovery of CD74, CD44, α4 integrin, Bcl-2, and NF-κB activation. Baicalein-induced reactive oxygen species activated the ASK1/JNK pathway with subsequent expression of TAp63. Pre-engagement with MIF/CD74 maintained the expression of CD74, CD44, and α4 integrin, as well as Syk/Src-mediated PI3K/Akt activation, in baicalein-treated EBV-transformed B cells. Meanwhile, ASK1/JNK-dependent TAp63 expression was efficiently suppressed after pre-treatment with MIF. Our results suggest that baicalein-mediated ASK1/JNK activation regulates the mitochondria-dependent apoptosis pathway through the up-regulation of TAp63 and down-regulation of NF-κB and CD74/CD44 in B-cell malignancies.
authors.affiliation: Department of Anatomy, Inje University College of Medicine, Busan, 614-735, Republic of Korea.|Ocular Neovascular Disease Research Center, Inje University Busan Paik Hospital, Busan, Republic of Korea.
authors.forename: Ga Bin
authors.initials: GB
authors.lastname: Park
authors.affiliation: Department of Anatomy, Inje University College of Medicine, Busan, 614-735, Republic of Korea.
authors.forename: Yeong Seok
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Inje University Busan Paik Hospital, Busan, 614-735, Republic of Korea.
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Department of Ophthalmology, Inje University Busan Paik Hospital, Busan, Republic of Korea.|Ocular Neovascular Disease Research Center, Inje University Busan Paik Hospital, Busan, Republic of Korea.
authors.forename: Jae Wook
authors.initials: JW
authors.lastname: Yang
authors.affiliation: Department of Anatomy, Inje University College of Medicine, Busan, 614-735, Republic of Korea. kimdj@inje.ac.kr.|Ocular Neovascular Disease Research Center, Inje University Busan Paik Hospital, Busan, Republic of Korea. kimdj@inje.ac.kr.
authors.forename: Daejin
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Inje University College of Medicine, Busan, 614-735, Republic of Korea. dyhur@inje.ac.kr.|Ocular Neovascular Disease Research Center, Inje University Busan Paik Hospital, Busan, Republic of Korea. dyhur@inje.ac.kr.
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Hur
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D044950:Flavanones / Q000494:pharmacology*; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D044950:Flavanones; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C006680:baicalein; D048848:MAP Kinase Kinase Kinase 5; D048670:MAP Kinase Kinase 4
keywords: ASK1; CD74; EBV-transformed B cells; Macrophage migration inhibitory factor; TAp63