Disease relevance of PTTG1

• INTERPRETATION: Increased tumour PTTG1 expression may be a marker of invasive colorectal carcinoma and could represent a new therapeutic target [1].
• FINDINGS: PTTG1 was overexpressed in all of 48 colon carcinomas (median fold-increase 2.2 [IQR 1.8-3.3]) and in 19 of 20 colonic polyps (2.2 [1.6-3.1]) compared with normal colonic tissue [1].
• METHODS: PTTG1 gene and protein expression were assessed in 68 colorectal tumours and compared with invasive characteristics, such as lymph-node invasion, evidence of metastases, tumour vessel density, and expression of basic fibroblast growth factor [1].
• PTIG1 gene silencing using siRNA may be an effective modality to treat liver cancer, in which PTTG1 is abundantly expressed [2].
• Ad.PTTG1-siRNA-mediated cytotoxic effect was dependent on expression levels of PTTG1 and p53 in hepatoma cell lines [2].
• Taken together, our data suggest that the reported overexpression of PTTG and PBF in differentiated thyroid cancer has profound implications for activity of the NIS gene, and hence significantly impacts upon the efficacy of radioiodine treatment [3].
• We also summarize the issue of PTTG expression and its correlation with clinicopathologic parameters in patients with neoplasms, particularly of endocrine organs [4].

High impact information on PTTG1

• Differently regulated APCs (APC(Cdh1), APC(Ama1)) have not been implicated in securin degradation at meiosis I [5].
• This is especially true of the anaphase promoting complex (APC), the machine that triggers chromosome segregation and the exit of mitosis by targeting securin and mitotic cyclins for destruction [6].
• Human securin interacts with p53 and modulates p53-mediated transcriptional activity and apoptosis [7].
• The PTTG1 protein is cell-cycle regulated and was identified as the human securin (a category of proteins involved in the regulation of sister-chromatid separation) on the basis of biochemical similarities with the Pds1p protein of budding yeast and the Cut2p protein of fission yeast [7].
• Moreover, we observed that transfection of H1299 cells with securin induced an accumulation of G2 cells that compensated for the loss of G2 cells caused by transfection with p53 [7].

Chemical compound and disease context of PTTG1

• Pituitary Tumor Transforming Gene (PTTG) Stimulates Thyroid Cell Proliferation via a Vascular Endothelial Growth Factor/Kinase Insert Domain Receptor/Inhibitor of DNA Binding-3 Autocrine Pathway [8].
• However, roles of securin and p53 on the oxaliplatin-induced cytotoxicity in human colorectal cancer cells remain unclear [9].
• CONCLUSION: We conclude that PTTG does not correlate with prolactin levels or tumor size in animal models of prolactinoma, and its pituitary content is not related to a decrease in dopaminergic control of the lactotrope, but may be influenced by estrogen action at the pituitary level [10].
• Immunohistochemical studies on formalin-fixed, paraffin-embedded tissues revealed hPTTG in 38.8% of B-cell lymphomas, 70.2% of T-cell lymphomas, and 73.1% of Hodgkin's lymphomas [11].
• Mice with Pttg inactivation exhibit pituitary hypoplasia, whereas targeted pituitary PTTG overexpression driven by alpha-subunit glycoprotein (alphaGSU) promoter results in focal pituitary hyperplasia [12].

Biological context of PTTG1

• Pituitary-tumour transforming gene (PTTG1) causes in-vitro and in-vivo transformation, regulates secretion of basic fibroblast growth factor, and inhibits chromatid separation [1].
• Adenovirus-mediated transfer of siRNA against PTTG1 inhibits liver cancer cell growth in vitro and in vivo [2].
• In conclusion, PTTG1 overexpressed in hepatoma cell lines negatively regulates the ability of p53 to induce apoptosis [2].
• We now determined direct effects of PTTG1 on hormonal phenotypes of functional pituitary tumor cells [13].
• The oncogenic potential of PTTG1 has been well characterized in the mouse, particularly mouse fibroblast (NIH3T3) cells, in which it induces cell proliferation, promotes tumor formation and angiogenesis [14].

Anatomical context of PTTG1

• Invasion of surrounding lymph nodes was associated with higher PTTG1 expression than in carcinomas limited to the bowel wall (3.4 [2.1-5.9] vs 1.9 [1.7-2.4], p=0.007), and higher PTTG1 expression was seen in more vascular than in less vascular tumours (2.6 [1.9-5.1] vs 1.9 [1.8-2.5], p=0.04) [1].
• Murine PTTG (mPTTG) is 66% homologous to human PTTG1 and PTTG-null (PTTG-/-) mice exhibit pancreatic beta-cell hypoplasia and abnormal nuclear morphology with resultant diabetes [15].
• Pituitary tumor transforming gene 1 (PTTG1) recently cloned from human testis is a potent oncogene and is highly expressed in all the tumors analyzed to date [16].
• In normal tissues, expression of PTTG1 mRNA was very low or undetectable except in testis, where PTTG1 mRNA was found to be localized to spermatocytes and spermatids [16].
• Our studies revealed a high level of expression of PTTG1 mRNA in both seminomatous and non-seminomatous testicular tumors; epithelial, sex-cord and stromal cell, and germ cell tumors of the ovary; and invasive ductal, ductal in situ and infiltrating ductal carcinoma of the breast [16].

Associations of PTTG1 with chemical compounds

• Estrogen (10 nm) treatment for 48 h partially restored PRL expression in stable wild-type PTTG1 C-terminal transfectants [13].
• To determine the cell types that express PTTG1 in normal and tumor tissues, we performed in situ hybridization using digoxigenin-labeled cRNA as a probe [16].
• Moreover, CM derived from hPTTG transfectants harboring a point mutation on the C-terminus proline-rich region of PTTG induced weaker angiogenic activity than WT-hPTTG-CM (P < 0.01) [17].
• Here we report that the expression of human securin is suppressed in cells treated with the DNA-damaging drugs doxorubicin and bleomycin [18].
• Glutathione S-transferase pull-down and co-immunoprecipitation assays demonstrate that PBF interacts specifically with PTTG under both in vitro and in vivo conditions [19].

Physical interactions of PTTG1

• Pull-down and co-immunoprecipitation assays demonstrated that p53 interacts specifically with securin both in vitro and in vivo [7].
• The PTTG binding domain in PBF was located within the C-terminal 30-amino acid region that contain a nuclear localization signal [19].
• Securin is an inhibitory protein that is bound to a protease called Separase to inhibit sister chromatid separation until the onset of anaphase [20].
• Using biotin-streptavidin pull-down assays, we confirmed Oct-1 binding to the two octamer motifs in the hPTTG1 promoter (-1669/-1631 and -1401/-1361) [21].

Regulatory relationships of PTTG1

• Securin also inhibits the ability of p53 to induce cell death [7].
• Separase is activated by the degradation of its inhibitor securin and by the removal of inhibitory phosphates [22].
• Human pituitary tumor-transforming gene (PTTG1) motif suppresses prolactin expression [13].
• In NT-2 cells, securin stimulated FGF-2 expression, which could be abrogated by a carboxyl-terminal mutation [23].
• Furthermore, in U87 cells PTTG expression was up-regulated by promalignant ligands epithelial growth factor (EGF) and TGFalpha, both at the protein and mRNA levels [24].

Other interactions of PTTG1

• We propose that the oncogenic effect of increased expression of securin may result from modulation of p53 functions [7].
• Regulation of human separase by securin binding and autocleavage [22].
• Because PTTG has been reported to induce angiogenesis, we investigated the effect of elevated Ca2+o on vascular endothelial growth factor (VEGF) expression [25].
• PCNA expression demonstrated that high securin levels in adult cortex were associated with absent cell proliferation [23].
• Another GPCR agonist, ADP, had no effect on PTTG expression [25].

Analytical, diagnostic and therapeutic context of PTTG1

• Forced expression of PTTG1 (securin) induces cellular transformation and promotes tumor development in animal models [2].
• We have used the reverse transcriptase-polymerase chain reaction technique to clone PTTG1 from ovarian tumors [16].
• Immunohistochemical and Western blot analysis for PTTG1 and ZNRD1 revealed increased protein level in RCC [26].
• RESULTS: We report that introduction of human PTTG1 into HEK293 cells through transfection with PTTG1 cDNA resulted in increased cell proliferation, anchorage-independent growth in soft agar, and formation of tumors after subcutaneous injection of nu/nu mice [14].
• In this study, we have used in situ hybridization and developmental Northern blot assays to demonstrate that PTTG mRNA is expressed stage-specifically in spermatocytes and spermatids during rat spermatogenic cycle [27].

References