Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pituitary tumor transforming (PTTG) gene family comprises PTTG1, 2, and 3. Forced expression of PTTG1 (securin) induces cellular transformation and promotes tumor development in animal models. PTTG1 is overexpressed in various human cancers. However, the expression and pathogenic implications of the PTTG gene family in hepatocellular carcinoma are largely unknown. Gene silencing using short interfering RNA (siRNA) has become an efficient means to study the functions of genes and has been increasingly used for cancer gene therapy approaches. We report that PTTG1, but not PTTG2 and 3, was highly and frequently expressed in liver cancer tissues from patients and highly in SH-J1, SK-Hep1, and Huh-7 hepatoma cell lines. Adenoviral vector encoding siRNA against PTTG1 (Ad.PTTG1-siRNA) depleted PTTG1 specifically and efficiently in SH-J1 hepatoma cells, which resulted in activation of p53 that led to increased p21 expression and induction of apoptosis. The depletion of PTTG1 in HCT116 colorectal cancer cells exhibited a cytotoxic effect in a p53-dependent manner. Ad.PTTG1-siRNA-mediated cytotoxic effect was dependent on expression levels of PTTG1 and p53 in hepatoma cell lines. Huh-7 hepatoma cells, once transduced with Ad.PTTG1-siRNA, displayed markedly attenuated growth potential in nude mice. Intra-tumor delivery of Ad.PTTG1-siRNA led to significant inhibition of tumor growth in SH-J1 tumor xenograft established in nude mice. In conclusion, PTTG1 overexpressed in hepatoma cell lines negatively regulates the ability of p53 to induce apoptosis. PTIG1 gene silencing using siRNA may be an effective modality to treat liver cancer, in which PTTG1 is abundantly expressed. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/ suppmat/index.html).
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PMID:Adenovirus-mediated transfer of siRNA against PTTG1 inhibits liver cancer cell growth in vitro and in vivo. 1662 36

Herein, we report the case of a 46-year-old male patient with only one month of double vision. Radiological examination revealed a pituitary tumor. Endocrinological investigations showed no pathological alterations of anterior pituitary function. Neuropathological examinations revealed a pituitary gland adenoma with an elevated proliferation rate (MIB-1 index 4-5 %) as well as an elevated p53 expression leading to the diagnosis of an atypical pituitary adenoma. Interestingly, the tumor exhibited strong basophilia in routine histology and densely secretory granules in electron microscopy (EM). However, no hormone excess was detectable in immunohistochemistry. In contrast to clinical and immunohistochemical observations, EM and routine histology findings implied a hormone production. This discrepancy might be due to a production of unfunctional pre-stages of pituitary gland proteins in this fast growing neoplasm.
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PMID:Atypical pituitary adenoma exhibiting densely secretory granules and basophilia without hormone production. 1664 9

Although pituitary tumors may be present in up to 10% of the population, the pathophysiology of these lesions is not well characterized. Pituitary tumors are composed of monoclonal cell populations with disrupted control of replication pathways. The oncogenes and tumor suppressor genes that are common in other malignancies (i.e. jun, fos, myc, and p53) are rarely involved in the development of these tumors. However, oncogenes, such as gsp, can be present in up to 40% of hormonally active adenomas. The process of pituitary oncogenesis further appears to involve oncogenes such as cyclin E, cyclin D1, and the pituitary tumor transforming gene (PTTG). Finally, the cAMP signaling cascade plays a significant role in generation of both benign and malignant pituitary tumors. In this review, the biology of pituitary adenomas is explored with a special emphasis on potential targets for the development of targeted therapeutics.
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PMID:Oncogenesis and mutagenesis of pituitary tumors. 1700 55

A 49-yr-old woman with a large pituitary tumor leading to visual loss and galactorrhea- amenorrhea was submitted to transcranial pituitary surgery, when a clinically nonfunctioning pituitary adenoma was partially removed. Histopathology and immunohistochemistry confirmed the diagnosis of "non-secreting atypical adenoma." At that time, serum and urinary free cortisol were normal, with low T4 levels and hyperprolactinemia. The patient was discharged on thyroxine and bromocriptine and treated with conventional radiotherapy. Two years later, she presented high free urinary cortisol levels and a positive ACTH response to desmopressin testing on dexametasone 2 mg overnight. A pituitary biopsy confirmed aggressive growth as well as positive immunoreactivity for ACTH, p53, Ki-67, and c-erb-B2. The patient was then treated with radiosurgery on ketoconazole therapy. The overall clinical, laboratory, and pathological data suggest a transition from a clinically nonfunctioning to a hypersecreting ACTH-producing tumor. Putative mechanisms of tumor transformation and the possibility of a silent corticotropinoma evolving into clinical Cushing s syndrome are discussed.
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PMID:Cushing's disease arising from a clinically nonfunctioning pituitary adenoma. 1715 52

Understanding factors subserving pituitary cell proliferation enables understanding mechanisms underlying uniquely benign pituitary tumors. Pituitary tumor-transforming gene (Pttg) deletion results in pituitary hypoplasia, low pituitary cell proliferation rates, and rescue of pituitary tumor development in Rb(+/-) mice. Pttg(-/-) pituitary glands exhibit ARF/p53/p21-dependent senescence pathway activation evidenced by up-regulated p19, cyclin D1, and Bcl-2 protein levels and p53 stabilization. High pituitary p21 levels in the absence of PTTG were associated with suppressed cyclin-dependent kinase 2 activity, Rb phosphorylation, and cyclin A expression, all required for cell cycle progression. Although senescence-associated beta-galactosidase was enhanced in Pttg-deficient pituitary glands, telomere lengths were increased. DNA damage signaling pathways were activated and aneuploidy was evident in the Pttg-deficient pituitary, triggering senescence-associated genes. To confirm the p21 dependency of decreased proliferation and senescence in the Pttg-null pituitary, mouse embryonic fibroblast (MEF) colony formation was tested in wild-type, Pttg(-/-), Rb(+/-), Rb(+/-)Pttg(-/-), and Rb(+/-)Pttg(-/-)p21(-/-) cells. Rb(+/-)Pttg(-/-) MEFs, unlike Rb(+/-) cells, failed to produce colonies and exhibited high levels of senescence. p21 deletion from Rb(+/-)Pttg(-/-) MEFs enhanced anchorage-independent cell growth, accompanied by a marked decrease in senescence. As cell proliferation assessed by bromodeoxyuridine incorporation was higher in Rb(+/-)Pttg(-/-)p21(-/-) relative to Rb(+/-)Pttg(-/-) pituitary glands, p21-dependent senescence provoked by Pttg deletion may underlie pituitary hypoplasia and decreased tumor development in Rb(+/-)Pttg(-/-) mice.
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PMID:Senescence mediates pituitary hypoplasia and restrains pituitary tumor growth. 1797 1

As commonly encountered, pituitary adenomas are invariably benign. We therefore studied protective pituitary proliferative mechanisms. Pituitary tumor transforming gene (Pttg) deletion results in pituitary p21 induction and abrogates tumor development in Rb(+/-)Pttg(-/-) mice. p21 disruption restores attenuated Rb(+/-)Pttg(-/-) pituitary proliferation rates and enables high penetrance of pituitary, but not thyroid, tumor growth in triple mutant animals (88% of Rb(+/-) and 72% of Rb(+/-)Pttg(-/-)p21(-/-) vs. 30% of Rb(+/-)Pttg(-/-) mice developed pituitary tumors, P < 0.001). p21 deletion also accelerated S-phase entry and enhanced transformation rates in triple mutant MEFs. Intranuclear p21 accumulates in Pttg-null aneuploid GH-secreting cells, and GH(3) rat pituitary tumor cells overexpressing PTTG also exhibited increased levels of mRNA for both p21 (18-fold, P < 0.01) and ATM (9-fold, P < 0.01). PTTG is abundantly expressed in human pituitary tumors, and in 23 of 26 GH-producing pituitary adenomas with high PTTG levels, senescence was evidenced by increased p21 and SA-beta-galactosidase. Thus, either deletion or overexpression of Pttg promotes pituitary cell aneuploidy and p53/p21-dependent senescence, particularly in GH-secreting cells. Aneuploid pituitary cell p21 may constrain pituitary tumor growth, thus accounting for the very low incidence of pituitary carcinomas.
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PMID:p21(Cip1) restrains pituitary tumor growth. 1898 26

Pituitary tumor-transforming gene-1 (PTTG1) is a transforming gene first discovered in rat pituitary tumor cells. It possesses transcriptional activity and also has securin functions. Chromatin immunoprecipitation-on-chip study reveals that PTTG1 is a global transcription factor, which exerts its transcriptional activity either by directly binding to DNA or by interacting with proteins including PTTG1 binding factor, p53, Sp1, and upstream stimulatory factor 1. PTTG1 has several validated transcriptional targets that are involved in different cellular processes. PTTG1 activates c-Myc in NIH 3T3 cells, suggesting a role in cell transformation. PTTG1 induces fibroblast growth factor 2 expression and promotes tumor angiogenesis.It binds to and inhibits p53 transcriptional activity. PTTG1 activates cyclin D3 and represses p21 expression, indicating a role in cell cycle regulation and cell senescence. Here, we review PTTG1 transcriptional targets and their functions.
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PMID:Transcriptional targets for pituitary tumor-transforming gene-1. 1943 93

Rb/E2F is dysregulated in murine and human pituitary tumors. Pituitary tumor transforming gene (PTTG1), a securin protein, is required for pituitary tumorigenesis, and PTTG1 deletion attenuates pituitary tumor development in Rb(+/-) mice. E2F1 and PTTG1 were concordantly overexpressed in 29 of 46 Rb(+/-) murine pituitary tissues and also in 45 of 80 human pituitary tumors (P < 0.05). E2F1 specifically bound the hPTTG1 promoter as assessed by chromatin immunoprecipitation and biotin-streptavidin pull-down assay, indicating that hPTTG1 may act as a direct E2F1 target. Transfection of E2F1 and its partner DP1 dose-dependently activated hPTTG1 transcription up to 3-fold in p53-devoid H1299 cells but not in p53-replete HCT116 cells. E2F1 overexpression enhanced endogenous hPTTG1 mRNA and protein levels up to 3-fold in H1299 cells. The presence of endogenous p53/p21 constrained the induction, whereas knocking down either p53 or p21 in HCT116 cells restored E2F1-induced hPTTG1 transactivation and expression. Moreover, suppressing Rb by small interfering RNA concordantly elevated E2F1 and hPTTG1 protein levels. In contrast, transfection of E2F1 small interfering RNA lowered hPTTG1 levels 24 h later in HCT116 than in H1299 cells, indicating that p53 delays E2F1 action on hPTTG1. These results elucidate a mechanism for abundant tumor hPTTG1 expression, whereby Rb inactivation releases E2F1 to induce hPTTG1. This signaling pathway may underlie the requirement of PTTG1 for pituitary tumorigenesis.
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PMID:E2F1 induces pituitary tumor transforming gene (PTTG1) expression in human pituitary tumors. 1983 43

Aberrant expression and mutations of thyroid hormone receptor genes (TRs) are closely associated with several types of human cancers. To test the hypothesis that TRs could function as tumor suppressors, we took advantage of mice with deletion of all functional TRs (TRalpha1(-/-)TRbeta(-/-) mice). As these mice aged, they spontaneously developed follicular thyroid carcinoma with pathological progression from hyperplasia to capsular invasion, vascular invasion, anaplasia and metastasis to the lung, similar to human thyroid cancer. Detailed molecular analysis revealed that known tumor promoters such as pituitary tumor-transforming gene were activated and tumor suppressors such as peroxisome proliferator-activated receptor gamma and p53 were suppressed during carcinogenesis. In addition, consistent with the human cancer, AKT-mTOR-p70(S6K) signaling and vascular growth factor and its receptor were activated to facilitate tumor progression. This report presents in vivo evidence that functional loss of both TRalpha1 and TRbeta genes promotes tumor development and metastasis. Thus, TRs could function as tumor suppressors in a mouse model of metastatic follicular thyroid cancer.
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PMID:Thyroid hormone receptors are tumor suppressors in a mouse model of metastatic follicular thyroid carcinoma. 2006 85

Despite the high prevalence of pituitary adenomas they are invariably benign, indicative of unique intrinsic mechanisms controlling pituitary cell proliferation. Cellular senescence is characterized by a largely irreversible cell cycle arrest and constitutes a strong anti-proliferative response, which can be triggered by DNA damage, chromosomal instability and aneuploidy, loss of tumor suppressive signaling or oncogene activation. In vivo senescence is an important protective mechanism against cancer. Here we discuss prospective mechanisms underlying senescence-associated molecular pathways activated in benign pituitary adenomas. Both deletion and over-expression of pituitary tumor transforming gene (Pttg) promote chromosomal instability and aneuploidy. Pttg deletion abrogates tumor development by activating p53/p21-dependent senescence pathways. Abundant PTTG in GH-secreting pituitary adenomas also triggers p21-dependent senescence. Pituitary p21 may therefore safeguard against further chromosomal instability by constraining pituitary tumor growth. These observations point to senescence as a target for effective therapy for both tumor silencing and growth restraint towards development of pituitary malignancy.
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PMID:Pituitary senescence: the evolving role of Pttg. 2015 4


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