title: Hepatic leukemia factor promotes resistance to cell death: implications for therapeutics and chronotherapy.
abstract: Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation.
authors: Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
authors: Katrina M
authors: KM
authors: Waters
authors: Ryan L
authors: RL
authors: Sontag
authors: Thomas J
authors: TJ
authors: Weber
mesh_terms: D000818:Animals; D017302:Annexins / Q000235:genetics; D017209:Apoptosis; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002940:Circadian Rhythm; D006801:Humans; D051379:Mice; D048629:Micronuclei, Chromosome-Defective; D009369:Neoplasms / Q000188:drug therapy / Q000209:etiology; D012333:RNA, Messenger / Q000032:analysis; D014161:Transduction, Genetic
chemical_list: D017302:Annexins; D050976:Basic-Leucine Zipper Transcription Factors; C490671:HLF protein, human; D012333:RNA, Messenger; D053148:Caspase 3