KLF5 Interacts with p53 in regulating survivin expression in acute lymphoblastic leukemia.
The Kruppel-like factor 5 (KLF5) is a transcription factor that regulates cellular signaling involved in cell proliferation and oncogenesis. Here, we report that KLF5 interacts with tumor suppressor p53 in regulating the expression of the inhibitor-of-apoptosis protein survivin, which may play a role in pathological process of cancer. The core promoter region of survivin contains multiple GT-boxes that have been characterized as KLF5 response elements. Deletion and mutation analyses as well as chromatin immunoprecipitation and electronic mobility shift assay indicated that KLF5 binds to the core survivin promoter and strongly induces its activity. Furthermore, we demonstrated that KLF5 protein is able to bind to p53 and abrogate the p53-regulated repression of survivin. Transfection of KLF5 into a KLF5-negative acute lymphoblastic leukemia cell line EU-8 enhanced survivin expression, and conversely, silencing of KLF5 by small interfering RNA in a KLF5-overexpressing acute lymphoblastic leukemia cell line EU-4 down-regulated survivin expression. The KLF5 small interfering RNA-mediated down-regulation of survivin sensitized EU-4 cells to apoptosis induced by chemotherapeutic drug doxorubicin. These findings identify a novel regulatory pathway for the expression of survivin under the control of KLF5 and p53. Deregulation of this pathway may result in overexpression of survivin in cancer, thus contributing to drug resistance.
Zhu
Ningxi
N
The Division of Pediatric Hematology/Oncology, Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, GA 30322, USA.
Gu
Lubing
L
Findley
Harry W
HW
Chen
Ceshi
C
Dong
Jin-Tang
JT
Yang
Lily
L
Zhou
Muxiang
M
D001483:Base Sequence; D001854:Bone Marrow Cells / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin