Transcription factor TFII-I causes transcriptional upregulation of GRP78 synthesis in prostate cancer cells

• Published in: Journal of cellular biochemistry 2009-02, Vol.106 (3), p.381-389
• Main Authors: Misra, U.K., Wang, F., Pizzo, S.V.
• Format: Article
• Language: English
• Subjects: alpha-Macroglobulins - pharmacology; Cell Line, Tumor; cell surface-associated GRP78; CHIP assays; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; gene silencing; Heat-Shock Proteins - biosynthesis; Heat-Shock Proteins - genetics; Humans; Male; Molecular Chaperones - biosynthesis; Molecular Chaperones - genetics; Phosphorylation; Phosphotyrosine - metabolism; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Binding; Protein Transport; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-fos - metabolism; RNA Interference; src-Family Kinases; TFII-I and GRP78 regulation; Transcription Factors, TFII - genetics; Transcription Factors, TFII - metabolism; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; transcriptional regulation; Up-Regulation - drug effects; Up-Regulation - genetics; α2-macroglobulin and signal transduction
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.22016

Receptor‐recognized forms of α2‐macroglobulin (α2M*) bind to cell surface‐associated GRP78 and induce proliferative and survival signaling in prostate cancer cells. As part of the cellular response to α2M*, 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 α2M*. This treatment caused a two‐ to threefold increase in TFII‐I and GRP78 synthesis from [35S]‐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 α2M*‐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 α2M* was followed by tyrosine phosphorylation of c‐Src as well as TFII‐I. We conclude that α2M*‐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. © 2008 Wiley‐Liss, Inc.