Wilms tumor suppressor 1 (WT1) and early growth response 1 (EGR1) are regulators of STIM1 expression.
Store-operated calcium entry (SOCE) is a key evolutionarily conserved process whereby decreases in endoplasmic reticulum Ca(2+) content lead to the influx of Ca(2+) across the plasma membrane. How this process is regulated in specific tumor cell types is poorly understood. In an effort to address this concern, we obtained and tested primary Wilms tumor cells, finding no detectable SOCE in this cell type. Analysis of the expression levels of STIM1 and ORAI1 (the molecular mediators of SOC) revealed poor STIM1 expression. Analysis of the STIM1 promoter using the TESS search system (University of Pennsylvania) revealed four putative response elements to the zinc-finger proteins WT1 (Wilms tumor suppressor 1) and EGR1 (early growth response 1). Either overexpression of WT1 or knockdown of EGR1 resulted in loss of STIM1 expression and a resultant decrease in SOCE. Furthermore, examination of Egr1 knock-out animals revealed loss of STIM1 expression in multiple tissues. Finally, using chromatin immunoprecipitation, we reveal direct binding of both WT1 and EGR1 to putative response elements located within 500 bp of the transcriptional start site of STIM1. Considering that WT1 and EGR1 are well described oncogenes and tumor suppressors, these observations may reveal new mechanisms responsible for distinct Ca(2+) signals in cancer cells.
Ritchie
Michael F
MF
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Yue
Chanyu
C
Zhou
Yandong
Y
Houghton
Peter J
PJ
Soboloff
Jonathan
J
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D051766:Early Growth Response Protein 1 / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071737:Stromal Interaction Molecule 1; D014407:Tumor Cells, Cultured; D025721:WT1 Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009396:Wilms Tumor / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D000951:Antigens, Neoplasm; D002352:Carrier Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; C454440:UBXN11 protein, human; D025721:WT1 Proteins; D008156:Luciferases; D002118:Calcium