Fas ligand gene expression is directly regulated by stress-inducible heat shock transcription factor-1.
Heat shock transcription factor-1 (HSF-1) is the primary stress responsive transcription factor that regulates expression of heat shock proteins (Hsps) in response to elevated temperature. We show that the transcriptional activity of HSF-1 can also directly mediate hyperthermia-induced Fas ligand (FasL) expression in activated T cells. We identify a conserved region within the human FasL promoter spanning from -276 to -236 upstream of the translational start site that contains two 15 bp non-identical adjacent HSF-1-binding sites or heat shock elements (HSEs) separated by 11 bp. Both the distal HSE (HSE1) (extending from -276 to -262) and the proximal HSE (HSE2) (spanning from -250 to -236) consist of two perfect and one imperfect nGAAn pentamers. We show the direct binding of HSF-1 to these elements and that mutation of these sites abrogates the ability of HSF-1 to bind and drive promoter activity. HSF-1 associates with these elements in a cooperative manner to mediate optimal promoter activity. We propose that the ability of HSF-1 to mediate stress-inducible expression of FasL extends its classical function as a regulator of Hsps to encompass a function for this transcription factor in the regulation of immune function and homeostasis.
Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
L
L
Bouchier-Hayes
S
S
McBride
C M
CM
van Geelen
S
S
Nance
L K
LK
Lewis
M J
MJ
Pinkoski
H M
HM
Beere
D001665:Binding Sites; D016923:Cell Death; D004268:DNA-Binding Proteins / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000235:genetics*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000235:genetics*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors