Kruppel-like factor 5 modulates p53-independent apoptosis through Pim1 survival kinase in cancer cells.
Although Kruppel-like factor 5 (KLF5) is a transcription factor that has been implicated in pathways critical to carcinogenesis, controversy persists as to whether it functions as a tumor suppressor or as an oncogene. Here, we describe a novel role for KLF5 in a p53-independent apoptotic pathway. Using RNA-interference technology, we show that cells deficient in KLF5 have increased sensitivity to DNA damage, regardless of p53 status. Both p53 and p53-dependent factors are unaffected by KLF5 depletion. Instead, the apoptotic phenotype consequent to damage is associated with reduced bad phosphorylation, and downregulation of Pim1. Consistently, transfection of wild-type Pim1 is sufficient to rescue this phenotype. Previous data have shown a number of putative Sp1-binding consensus sequences on the Pim1 promoter. Remarkably, chromatin immunoprecipitation studies show that KLF5 binds to the Pim1 promoter, and that binding increases soon after damage. These results identify a novel, p53-independent apoptotic pathway through which KLF5 functions in response to DNA damage. Therapeutic deregulation of this pathway could be used to modulate chemosensitivity.
Zhao
Y
Y
Wee Kim Wee Laboratory of Surgical Oncology, Department of Surgical Oncology, National Cancer Centre, Singapore.
Hamza
M S
MS
Leong
H S
HS
Lim
C-B
CB
Pan
Y-F
YF
Cheung
E
E
Soo
K-C
KC
Iyer
N G
NG
D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D004249:DNA Damage / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D051573:Proto-Oncogene Proteins c-pim-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051025:bcl-Associated Death Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D016159:Tumor Suppressor Protein p53; D051025:bcl-Associated Death Protein; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1