1. Kruppel-like factor 5 modulates p53-independent apoptosis through Pim1 survival kinase in cancer cells
- Author
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Chuan Bian Lim, Leong Hs, Iyer Ng, Soo Kc, Pan Yf, Hamza Ms, Edwin Cheung, and Yan Zhao
- Subjects
Cancer Research ,Tumor suppressor gene ,DNA damage ,Cell Survival ,Kruppel-Like Transcription Factors ,PIM1 ,Apoptosis ,Biology ,medicine.disease_cause ,Transfection ,Proto-Oncogene Proteins c-pim-1 ,Genetics ,medicine ,Humans ,Phosphorylation ,Molecular Biology ,Transcription factor ,HCT116 Cells ,Cancer cell ,Cancer research ,bcl-Associated Death Protein ,Tumor Suppressor Protein p53 ,Carcinogenesis ,Apoptosis Regulatory Proteins ,Chromatin immunoprecipitation ,DNA Damage ,Protein Binding ,Signal Transduction - Abstract
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.
- Published
- 2007