Transcription factor TFII-I causes transcriptional upregulation of GRP78 synthesis in prostate cancer cells.
Receptor-recognized forms of alpha(2)-macroglobulin (alpha(2)M*) bind to cell surface-associated GRP78 and induce proliferative and survival signaling in prostate cancer cells. As part of the cellular response to alpha(2)M*, GRP78 expression is itself upregulated. In response to other stimuli, the transcription factor TFII-I upregulates GRP78 by binding to its gene promoter. We have, therefore, studied the role of TFII-I in transcriptional upregulation of GRP78 in 1-LN human prostate cancer cells stimulated with alpha(2)M*. This treatment caused a two- to threefold increase in TFII-I and GRP78 synthesis from [(35)S]-labeled precursor amino acids. Synthesis of both TFII-I and GRP78 were significantly reduced by silencing TFII-I gene expression or pretreatment of cells with genistein or actinomycin D. Confocal microscopy was employed to demonstrate relocation of TFII-I to the nucleus. In alpha(2)M*-stimulated cells, moreover, TFII-I bound to the GRP78 promoter as determined by CHIP assay. We also demonstrate binding of TFII-I to the c-fos promoter, consistent with its role in upregulating c-fos gene expression. In non-lymphoid cells, phosphorylated c-Src is an activator of TFII-I. Ligation of GRP78 on 1-LN cells with alpha(2)M* was followed by tyrosine phosphorylation of c-Src as well as TFII-I. We conclude that alpha(2)M*-induced increase in GRP78 synthesis is caused by transcriptional upregulation of TFII-I which binds to the GRP78 promoter and thus potentiates its cell survival and antipoptotic functions in 1-LN prostate cancer cells.
Misra
U K
UK
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Wang
F
F
Pizzo
S V
SV
D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000096:biosynthesis / Q000235:genetics*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D034622:RNA Interference; D019473:Transcription Factors, TFII / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D000511:alpha-Macroglobulins / Q000494:pharmacology; D019061:src-Family Kinases
D000091342:Endoplasmic Reticulum Chaperone BiP; C104259:GTF2I protein, human; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D019473:Transcription Factors, TFII; D000511:alpha-Macroglobulins; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human