Journal Article

Antiproliferative B cell translocation gene 2 protein is down-regulated post-transcriptionally as an early event in prostate carcinogenesis

Michael A. Ficazzola, Mitchell Fraiman, Jordan Gitlin, Kenneth Woo, Jonathan Melamed, Mark A. Rubin and Paul D. Walden

in Carcinogenesis

Volume 22, issue 8, pages 1271-1279
Published in print August 2001 | ISSN: 0143-3334
Published online August 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.8.1271
Antiproliferative B cell translocation gene 2 protein is down-regulated post-transcriptionally as an early event in prostate carcinogenesis

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B cell translocation gene 2 (BTG2) is a p53 target that negatively regulates cell cycle progression in response to DNA damage and other stress. The objective of this study was to examine the expression, regulation and tumor suppressor properties of BTG2 in prostate cells. By immunohistochemistry BTG2 protein was detected in ~50% of basal cells in benign glands from the peripheral zone of the human prostate. BTG2 was expressed in all hyperproliferative atrophic peripheral zone lesions examined (simple atrophy, post-atrophic hyperplasia and proliferative inflammatory atrophy), but was undetectable or detectable at very low levels in the hyperproliferative epithelial cells of HGPIN and prostate cancer. BTG2 mRNA was detected in non-malignant prostate epithelial (PE) cells and in LNCaP cells, but not in PC-3 cells, consistent with p53-dependent regulation. In PE cells BTG2 protein was detected in areas of cell confluence by immunohistochemistry. BTG2 protein in LNCaP cells was undetectable by immunohistochemistry but was detected by immunoblotting at 8- to 9-fold lower levels than in PE cells. BTG2 protein levels were shown to be regulated by the ubiquitin–proteosome system. Forced expression of BTG2 in PC-3 cells was accompanied by a decreased rate of cell proliferation and decreased tumorigenicity of these cells in vivo. Taken together, these findings suggest that BTG2 functions as a tumor suppressor in prostate cells that is activated by cell quiescence, cell growth stimuli as part of a positive feedback mechanism and in response to DNA damage or other cell stress. The low steady-state levels of BTG2 protein in HGPIN and prostate cancer, a potential consequence of increased proteosomal degradation, may have important implications in the initiation and progression of malignant prostate lesions. Furthermore, these findings suggest that a significant component of the p53 G1 arrest pathway might be inactivated in prostate cancer even in the absence of genetic mutations in p53.

Keywords: BPH, benign prostatic hyperplasia; BTG, B cell translocation gene; CDK, cyclin-dependent kinase; DHT, dihydrotestosterone; FBS, fetal bovine serum; PAH, post-atrophic hyperplasia; PE, prostate-derived epithelial; PIA, proliferative inflammatory atrophy; pRb, retinoblastoma protein; PSA, prostate-specific antigen.

Journal Article.  8861 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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