Disease relevance of BTG2

• BTG2 expression was found to be significantly reduced in a large proportion of human kidney and breast carcinomas, suggesting that BTG2 is a tumor suppressor that links p53 and Rb pathways in human tumorigenesis [1].
• Loss of nuclear BTG2 expression in estrogen receptor-alpha (ERalpha)-positive breast tumors correlated significantly with increased histologic grade and tumor size [2].
• 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 [3].
• The BTG2/TIS21/PC3 gene is an antiproliferative gene which maps within a chromosomal segment (1q32) frequently altered in breast adenocarcinomas [4].
• The neurogene BTG2TIS21/PC3 is transactivated by DeltaNp73alpha via p53 specifically in neuroblastoma cells [5].

High impact information on BTG2

• We show that BTG2 expression is induced through a p53-dependent mechanism and that BTG2 function may be relevant to cell cycle control and cellular response to DNA damage [6].
• Pc3/Tis21 has a strong sequence similarity to the human antiproliferative BTG1 gene cloned from a chromosomal translocation of a B-cell chronic lymphocytic leukaemia [6].
• The rodent Pc3/Tis21 gene was initially described as an immediate early gene induced by tumour promoters and growth factors in PC12 and Swiss 3T3 cells [6].
• Repression of BTG2 results in up-regulation of cyclins D1 and E1 and phosphorylation of Rb and, in cooperation with other oncogenic elements, induces neoplastic transformation of primary human fibroblasts [1].
• To test this hypothesis, we investigated the effect of COX-2 depletion on apoptosis and performed a structure-activity analysis of the COX-2 inhibitor celecoxib in the androgen-independent prostate cancer cell line PC-3 [7].

Chemical compound and disease context of BTG2

• An androgen-independent androgen receptor function protects from inositol hexakisphosphate toxicity in the PC3/PC3(AR) prostate cancer cell lines [8].
• Tributyrin-treated tumours showed the strongest effect with 38% apoptotic nuclei in the prostate cancer cell line PC3 [9].
• Furthermore, combined treatment with antisense clusterin oligodeoxynucleotide, Ad5CMV-p53, and mitoxantrone completely eradicated s.c. PC3 tumors and lymph node metastases from orthotopic PC3 tumors in 60% and 100% of mice, respectively [10].
• Furthermore, treatment of mice bearing the PTEN-negative PC-3 prostate cancer xenografts with CCI-779, an ester of rapamycin in clinical development combined with doxorubicin, inhibited the growth of the doxorubicin-resistant PC-3 tumors confirming the observations in vitro [11].
• In addition, prostate cancer cell lines without PSA expression (PC-3 and DU-145) did not show iodide uptake activity when transfected with NIS/PSA-pEGFP-1 [12].

Biological context of BTG2

• Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway [6].
• BTG1 and BTG2 belong to a family of functionally related genes involved in the control of the cell cycle [13].
• Both BTG1 and BTG2 are involved in cell-growth control [14].
• In rat mammary glands, BTG2 is expressed in epithelial cells and levels decreased during pregnancy and lactation but recovered during involution [15].
• 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 [3].

Anatomical context of BTG2

• The B-cell translocation gene-2 (BTG2) is present in the nuclei of epithelial cells in many tissues, including the mammary gland where its expression is regulated during glandular proliferation and differentiation in pregnancy [2].
• BTG2 expression is regulated by p53, and its inactivation in embryonic stem cells leads to the disruption of DNA damage-induced G2/M cell-cycle arrest [14].
• BTG2 expression was very low or undetectable in human breast cancer cell lines compared with nontumorigenic mammary epithelial cells, and nuclear expression of BTG2 was absent in 65% of human breast tumors compared with adjacent matched normal glands [15].
• BTG2 mRNA was expressed in primary cultures of both cell types, but more abundantly in epithelial cells [16].
• Experimental overexpression of the BTG2 gene in NIH3T3 and PC12 cells leads to a partial inhibition of cell proliferation [17].

Associations of BTG2 with chemical compounds

• Estrogen and progestin suppress BTG2 expression, suggesting that these steroids, which stimulate proliferation and lobuloalveolar development of mammary epithelial cells, may downregulate BTG2 in the mammary gland during pregnancy [15].
• Phosphorylation of serine 147 of tis21/BTG2/pc3 by p-Erk1/2 induces Pin-1 binding in cytoplasm and cell death [18].
• When the cells were synchronized by nocodazole, TIS21 overexpressers inhibited degradations of cyclin A and cyclin B1 in 3 h after release from the synchronization [19].
• In the absence of retinoic acid, BTG2 is present in the RARalpha transcriptional complex, together with the arginine methyltransferase PRMT1 and Sin3A [20].
• Overall, our data show that BTG2 contributes to retinoic acid activity by favoring differentiation through a gene-specific modification of histone H4 arginine methylation and acetylation levels [20].

Physical interactions of BTG2

• BTG2 antiproliferative protein interacts with the human CCR4 complex existing in vivo in three cell-cycle-regulated forms [21].
• Furthermore, tis21 was bound to cyclin B1 and Cdc2 and inhibited its activity in vivo and in vitro [18].
• Our results suggest a potential competition between TIS21 and PKC for binding to PICK1 [22].
• Additionally, we identify a RA response element in the Btg2 promoter and show that the element binds retinoid X receptor/RAR heterodimers in vitro, is occupied by the heterodimers in cells, and can drive RA-induced activation of a reporter gene [23].
• Overexpressed BTG2 increases PRMT1 participation in the RARalpha protein complex on the RARbeta promoter, a target gene model, and enhances gene-specific histone H4 arginine methylation [20].

Regulatory relationships of BTG2

• Transfection of tis21 significantly enhanced EGF-induced Pin-1 diffusion to cytoplasm, compared with that in the vector-transfected cells [18].
• We further showed that MDM2 overexpression abrogated genistein-induced apoptosis in vitro and that genistein inhibited MDM2 expression and tumor growth in PC3 xenografts [24].
• RESULTS: Out of the three human prostate cancer cell lines tested, DU-145 and PC3 but not LNCaP cells expressed detectable amount of HOXC8 transcripts [25].
• We show here that retinoic acid treatment of hematopoietic cells induces the expression of BTG2 [20].

Other interactions of BTG2

• As part of an ongoing attempt to understand their biological functions, we used a yeast two-hybrid screening to look for possible functional partners of Btg1 and Btg2 [13].
• Moreover, we show that hCCR4, as well as hCAF1 and BTG2, modulate the transcription regulation mediated by ERalpha [21].
• Thus, it can be concluded that the C-terminal regions are necessary and sufficient to control the stabilities of BTG1, BTG2, Tob, and Tob2 proteins [26].
• Our data indicate that Btg1 and Btg2 act as transcriptional cofactors of the Hoxb9 protein, and suggest that this interaction may mediate their antiproliferative function [13].
• TIS21 protein modulates the enzymatic activity of recombinant GST-PRMT1 fusion protein but not the activity of GST-PRMT3 [27].

Analytical, diagnostic and therapeutic context of BTG2

• In PE cells BTG2 protein was detected in areas of cell confluence by immunohistochemistry [3].
• 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 [3].
• Signal transducer and activator of transcription 3 (STAT3) is activated, as determined by electrophoretic motility shift assays, by EGFR in DU145 and PC3 human prostate carcinoma cells in addition to the motility model NR6 fibroblast cell line [28].
• Based on the previous report that the expression of TIS21 is involved in the induction of senescence after chemotherapy of cancer cells, which can be a mechanism to resist carcinogenesis, TIS21(/BTG2/PC3), the endogenous cell death molecule and pan-cell cycle regulator, might be a link between cellular senescence and carcinogenesis [29].
• Cell culture experiments demonstrated that BTG2 expression was weakly inducible by the phorbolester 12-O-tetradecanoylphorbol-13-acetate in one of four cRCC cell lines [30].

References