Transcription Factor TFII-I Causes Transcriptional Upregulation of GRP78 Synthesis in Prostate Cancer Cells

Receptor-recognized forms of alpha(2)-macroglobulin (alpha M-2*) bind to cell surface-associated GRP78 and induce proliferative and survival signaling in prostate cancer cells. As part of the cellular response to alpha M-2*, 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 M-2*. This treatment caused a two- to threefold increase in TFII-I and GRP78 synthesis from [S-35]-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 M-2*-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 M-2* was followed by tyrosine phosphorylation of c-Src as well as TFII-I. We conclude that alpha M-2*-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. J. Cell. Biochem. 106: 381-389, 2009. (C) 2008 Wiley-Liss, Inc.