title: Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli.
abstract: The epidermis is continually exposed to harmful mutagens that have the potential to cause DNA damage. To protect the skin from accumulating mutated cells, keratinocytes have developed a highly regulated mechanism of eliminating damaged cells through apoptosis. Bcl-xL is a well-described cell survival protein that when overexpressed in skin can protect keratinocytes from UV radiation-induced apoptosis. To begin to unravel the complex mechanisms that keratinocytes use to survive, we wanted to characterize the role of endogenous Bcl-xL in protecting cells from death. In this study, we describe the development and characterization of an antisense inhibitor to Bcl-xL. We show that this inhibitor reduces Bcl-xL RNA and protein in a concentration-dependent, sequence-specific manner. Furthermore, treatment of keratinocytes and epithelial cells with this inhibitor sensitizes these cells to UV-B radiation and cisplatinum treatment-induced apoptosis. Thus, these results offer direct evidence that Bcl-xL is critical in the protection of skin and epithelial cells from apoptosis and provide a basis for the role of Bcl-xL in keratinocyte and epithelial cell survival.
authors.affiliation: Department of Pharmacology, Isis Pharmaceuticals, Carlsbad, California 92008, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Taylor
authors.forename: Q Q
authors.initials: QQ
authors.lastname: Zhang
authors.forename: B P
authors.initials: BP
authors.lastname: Monia
authors.forename: E G
authors.initials: EG
authors.lastname: Marcusson
authors.forename: N M
authors.initials: NM
authors.lastname: Dean
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D003001:Cloning, Molecular; D004171:Diploidy; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000528:radiation effects; D018922:HL-60 Cells; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000528:radiation effects; D008175:Lung Neoplasms; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000166:cytology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D051020:bcl-X Protein
chemical_list: C494811:BCL2L1 protein, human; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D002945:Cisplatin