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ABSTRACT: Pituitary tumor-transforming gene (PTTG), the index mammalian securin, is abundantly expressed in several tumors and regulates tumor growth and progression. Molecular mechanisms elucidating PTTG regulation and actions remain elusive. Here, we provide evidence that PTTG acts as a signal transducer and activator of transcription factor 3 (STAT3) target gene. Total STAT3 and Tyr705 phosphorylated STAT3 were concordantly expressed with PTTG in human colorectal tumors (n=97 and n=95, respectively, P<0.001). STAT3 specifically bound the human PTTG promoter and induced PTTG transcriptional activity (twofold) as assessed by chromatin immunoprecipitation and luciferase reporter assays. STAT3 transfection increased PTTG mRNA and protein abundance twofold in HCT116 human colon cancer cells, and induction was further enhanced (threefold) by constitutively active STAT3 (STAT3-C), whereas strongly abrogated by dominant-negative STAT3 (STAT3-DN). Attenuating PTTG expression by siRNA in STAT3 HCT116 stable transfectants suppressed cell growth and colony formation in vitro, and PTTG cell knockout also constrained activated STAT3-induced explanted murine tumor growth in vivo. STAT3 increased HCT116 cell migration and invasion up to fivefold, whereas cell mobility was abolished by STAT3-DN (>85%). Impairing PTTG expression by siRNA also strongly suppressed STAT3-faciliated cell migration and invasion by up to 90%. Knocking out PTTG in STAT3-C HCT116 stable transfectants strongly decreased tumor metastases in nude mice, indicating the requirement of PTTG for STAT3-promoted metastasis. These results elucidate a mechanism for tumor cell PTTG regulation, whereby STAT3 induces PTTG expression to facilitate tumor growth and metastasis, and further support the rationale for targeting PTTG to abrogate colorectal cancer growth.Oncogene advance online publication, 18 February 2013; doi:10.1038/onc.2013.16.
Oncogene 02/2013; · 6.37 Impact Factor
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ABSTRACT: In March 2011, the Acromegaly Consensus Group met to revise and update the guidelines on the diagnosis and treatment of acromegaly complications. The meeting was sponsored by the Pituitary Society and the European Neuroendocrinology Association and included experts skilled in the management of acromegaly. Complications considered included cardiovascular, endocrine and metabolic, sleep apnea, bone diseases, and mortality. Outcomes in selected, related clinical conditions were also considered, and included pregnancy, familial acromegaly and invasive macroadenomas. The need for a new disease staging model was considered, and design of such a tool was proposed.
Pituitary 08/2012; · 1.83 Impact Factor
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ABSTRACT: Although acromegaly is a rare disease, the clinical, economic and health-related quality of life (HRQoL) burden is considerable due to the broad spectrum of comorbidities as well as the need for lifelong management. We performed a comprehensive literature review of the past 12 years (1998-2010) to determine the benefit of disease control (defined as a growth hormone [GH] concentration <2.5 μg/l and insulin-like growth factor [IGF]-1 normal for age) on clinical, HRQoL, and economic outcomes. Increased GH and IGF-1 levels and low frequency of somatostatin analogue use directly predicted increased mortality risk. Clinical outcome measures that may improve with disease control include joint articular cartilage thickness, vertebral fractures, left ventricular function, exercise capacity and endurance, lipid profile, and obstructive apnea events. Some evidence suggests an association between controlled disease and improved HRQoL. Total direct treatment costs were higher for patients with uncontrolled compared to controlled disease. Costs incurred for management of comorbidities, and indirect cost could further add to treatment costs. Optimizing disease control in patients with acromegaly appears to improve outcomes. Future studies need to evaluate clinical outcomes, as well as HRQoL and comprehensive economic outcomes achieved with controlled disease.
Pituitary 05/2011; 14(3):284-94. · 1.83 Impact Factor
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ABSTRACT: To determine whether peer-reviewed consensus statements have changed clinical practice, we surveyed acromegaly care in specialist centers across the globe, and determined the degree of adherence to published consensus guidelines on acromegaly management. Sixty-five acromegaly experts who participated in the 7th Acromegaly Consensus Workshop in March 2009 responded. Results indicated that the most common referring sources for acromegaly patients were other endocrinologists (in 26% of centers), neurosurgeons (25%) and primary care physicians (21%). In sixty-nine percent of patients, biochemical diagnoses were made by evaluating results of a combination of growth hormone (GH) nadir/basal GH and elevated insulin like growth factor-I (IGF-I) levels. In both Europe and the USA, neurosurgery was the treatment of choice for GH-secreting microadenomas and for macroadenomas with compromised visual function. The most widely used criteria for neurosurgical outcome assessment were combined measurements of IGF-I and GH levels after oral glucose tolerance test (OGTT) 3 months after surgery. Ninety-eight percent of respondents stated that primary treatment with somatostatin receptor ligands (SRLs) was indicated at least sometime during the management of acromegaly patients. In nearly all centers (96%), the use of pegvisomant monotherapy was restricted to patients who had failed to achieve biochemical control with SRL therapy. The observation that most centers followed consensus statement recommendations encourages the future utility of these workshops aimed to create uniform management standards for acromegaly.
Pituitary 11/2010; 14(2):125-33. · 1.83 Impact Factor
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ABSTRACT: The Acromegaly Consensus Group met in April 2009 to revisit the guidelines on criteria for cure as defined in 2000.
Participants included 74 neurosurgeons and endocrinologists with extensive experience of treating acromegaly. EVIDENCE/CONSENSUS PROCESS: Relevant assays, biochemical measures, clinical outcomes, and definition of disease control were discussed, based on the available published evidence, and the strength of consensus statements was rated.
Criteria to define active acromegaly and disease control were agreed, and several significant changes were made to the 2000 guidelines. Appropriate methods of measuring and achieving disease control were summarized.
The Journal of clinical endocrinology and metabolism 07/2010; 95(7):3141-8. · 6.50 Impact Factor
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S Petersenn,
J Schopohl,
A Barkan,
P Mohideen,
A Colao,
R Abs,
A Buchelt,
Y-Y Ho,
K Hu,
A J Farrall, S Melmed,
B M K Biller
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ABSTRACT: Pasireotide (SOM230) is a novel multireceptor ligand somatostatin analog with affinity for somatostatin receptor subtypes sst(1-3) and sst(5). Because most GH-secreting pituitary adenomas express sst(2) and sst(5), pasireotide has the potential to be more effective than the sst(2)-preferential somatostatin analogs octreotide and lanreotide.
Our objective was to evaluate the efficacy and safety of three different doses of pasireotide in patients with acromegaly.
We conducted a phase II, randomized, multicenter, open-label, three-way, crossover study.
Sixty patients with acromegaly, defined by a 2-h five-point mean GH level higher than 5 microg/liter, lack of suppression of GH to less than 1 microg/liter after oral glucose tolerance test, and elevated IGF-I for age- and sex-matched controls. Patients could have had previous surgery, radiotherapy, and/or medical therapy or no previous treatment.
After treatment with octreotide 100 microg s.c. three times daily for 28 d, each patient received pasireotide 200, 400, and 600 microg s.c. twice daily in random order for 28 d.
A biochemical response was defined as a reduction in GH to no more than 2.5 microg/liter and normalization of IGF-I to age- and sex-matched controls.
After 4 wk of octreotide, 9% of patients achieved a biochemical response. After 4 wk of pasireotide 200-600 microg s.c. bid, 19% of patients achieved a biochemical response, which increased to 27% after 3 months of pasireotide; 39% of patients had a more than 20% reduction in pituitary tumor volume. Pasireotide was generally well tolerated.
Pasireotide is a promising treatment for acromegaly. Larger studies of longer duration evaluating the efficacy and safety of pasireotide in patients with acromegaly are ongoing.
The Journal of clinical endocrinology and metabolism 06/2010; 95(6):2781-9. · 6.50 Impact Factor
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S Melmed,
A Colao,
A Barkan,
M Molitch,
A B Grossman,
D Kleinberg,
D Clemmons,
P Chanson,
E Laws,
J Schlechte,
M L Vance,
K Ho,
A Giustina
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ABSTRACT: The Acromegaly Consensus Group reconvened in November 2007 to update guidelines for acromegaly management.
The meeting participants comprised 68 pituitary specialists, including neurosurgeons and endocrinologists with extensive experience treating patients with acromegaly. EVIDENCE/CONSENSUS PROCESS: Goals of treatment and the appropriate imaging and biochemical and clinical monitoring of patients with acromegaly were enunciated, based on the available published evidence.
The group developed a consensus on the approach to managing acromegaly including appropriate roles for neurosurgery, medical therapy, and radiation therapy in the management of these patients.
The Journal of clinical endocrinology and metabolism 03/2009; 94(5):1509-17. · 6.50 Impact Factor
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M Boscaro,
W H Ludlam,
B Atkinson,
J E Glusman,
S Petersenn,
M Reincke,
P Snyder,
A Tabarin,
B M K Biller,
J Findling, S Melmed,
C H Darby,
K Hu,
Y Wang,
P U Freda,
A B Grossman,
L A Frohman,
J Bertherat
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ABSTRACT: There is currently no medical therapy for Cushing's disease that targets the pituitary adenoma. Availability of such a medical therapy would be a valuable therapeutic option for the management of this disorder.
Our objective was to evaluate the short-term efficacy of the novel multireceptor ligand somatostatin analog pasireotide in patients with de novo, persistent, or recurrent Cushing's disease.
We conducted a phase II, proof-of-concept, open-label, single-arm, 15-d multicenter study.
Thirty-nine patients with either de novo Cushing's disease who were candidates for pituitary surgery or with persistent or recurrent Cushing's disease after surgery without having received prior pituitary irradiation. Intervention: Patients self-administered sc pasireotide 600 microg twice daily for 15 d.
Normalization of urinary free cortisol (UFC) levels after 15 d treatment was the main outcome measure.
Of the 29 patients in the primary efficacy analysis, 22 (76%) showed a reduction in UFC levels, of whom five (17%) had normal UFC levels (responders), after 15 d of treatment with pasireotide. Serum cortisol levels and plasma ACTH levels were also reduced. Steady-state plasma concentrations of pasireotide were achieved within 5 d of treatment. Responders appeared to have higher pasireotide exposure than nonresponders.
Pasireotide produced a decrease in UFC levels in 76% of patients with Cushing's disease during the treatment period of 15 d, with direct effects on ACTH release. These results suggest that pasireotide holds promise as an effective medical treatment for this disorder.
Journal of Clinical Endocrinology & Metabolism 11/2008; 94(1):115-22. · 6.50 Impact Factor
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A Giustina,
A Barkan,
P Chanson,
A Grossman,
A Hoffman,
E Ghigo,
F Casanueva,
A Colao,
S Lamberts,
M Sheppard, S Melmed
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ABSTRACT: The V Consensus Group Meeting on 'Guidelines for Treatment of GH Excess and GH Deficiency in the Adult' was an international workshop held on February 20-22, 2006 in Santa Monica, California, USA. The principal aim of this meeting was to provide guidelines for the evaluation and treatment of adults with either form of abnormal GH secretion: GH excess or GH deficiency. The workshop included debates as to the choice of primary treatment, discussions of the targets for adequate treatment, and concluded with presentations on open issues germane to adult GH treatment including the role of GH in malignancies, the impact of longterm treatment on bone, and a cost-benefit analysis. The meeting was comprised of 66 delegates representing 13 different countries.
Journal of endocrinological investigation 10/2008; 31(9):820-38. · 1.57 Impact Factor
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B M K Biller,
A B Grossman,
P M Stewart, S Melmed,
X Bertagna,
J Bertherat,
M Buchfelder,
A Colao,
A R Hermus,
L J Hofland, [......],
J R Lindsay,
J Newell-Price,
L K Nieman,
S Petersenn,
N Sonino,
G K Stalla,
B Swearingen,
M L Vance,
J A H Wass,
M Boscaro
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ABSTRACT: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing's syndrome, because there is no recent consensus on the management of this rare disorder.
Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing's syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing's disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing's disease, and 5) management of ectopic ACTH syndrome, Nelson's syndrome, and special patient populations.
Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking.
Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority.
ACTH-dependent Cushing's syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing's syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing's disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing's syndrome, early diagnosis and prompt therapy are warranted.
Journal of Clinical Endocrinology & Metabolism 08/2008; 93(7):2454-62. · 6.50 Impact Factor
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ABSTRACT: Pituitary tumor transforming gene 1 (PTTG1), a transforming gene highly expressed in several cancers, is a mammalian securin protein regulating both G1/S and G2/M phases. Using protein array screening, we showed PTTG1 interacting with Aurora kinase A (Aurora-A), and confirmed the interaction using co-immunoprecipitation, His-tagged pull-down assays and intracellular immunofluorescence colocalization. PTTG1 transfection into HCT116 cells prevented Aurora-A T288 autophosphorylation, inhibited phosphorylation of the histone H3 Aurora-A substrate and resulted in abnormally condensed chromatin. PTTG1-null cell proliferation was more sensitive to Aurora-A knock down and to Aurora kinase Inhibitor III treatment. The results indicate that PTTG1 and Aurora-A interact to regulate cellular responses to anti-neoplastic drugs. PTTG1 knockdown is therefore a potential approach to improve the efficacy of tumor Aurora kinase inhibitors.
Oncogene 08/2008; 27(49):6385-95. · 6.37 Impact Factor
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ABSTRACT: Pituitary tumor transforming gene (PTTG1) was isolated from rat pituitary tumor cells, and subsequently identified as a securin protein as well as a transcription factor. We show here a global transcriptional effect of PTTG1 in human choriocarcinoma JEG-3 cells by simultaneously assessing 20,000 gene promoters using chromatin immunoprecipitation (ChIP)-on-Chip experiments. Seven hundred and forty-six gene promoters (P<0.001) were found enriched, with functions relating to cell cycle, metabolic control and signal transduction. Significant interaction between PTTG1 and Sp1 (P<0.000001) was found by transcriptional pattern analysis of ChIP data and further confirmed by immunoprecipitation and pull-down assays. PTTG1 acts coordinately with Sp1 to induce cyclin D3 expression approximately threefold, and promotes G1/S-phase transition independently of p21. PTTG1 deletion was also protective for anchorage-independent cell colony formation. The results show that PTTG1 exhibits properties of a global transcription factor, and specifically modulates the G1/S-phase transition by interacting with Sp1. This novel signaling pathway may be required for PTTG1 transforming activity.
Oncogene 08/2007; 26(38):5596-605. · 6.37 Impact Factor
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ABSTRACT: PTTG1, a securin protein, also behaves as a transforming gene and is overexpressed in pituitary tumors. Because pituitary folliculostellate (FS) cells regulate pituitary tumor growth factors by paracrine mechanisms, epidermal growth factor (EGF) receptor (EGFR)-mediated PTTG1 expression and cell proliferation was tested in pituitary FS TtT/GF cells. EGFR ligands caused up to 3-fold induction of Pttg1 mRNA expression, enhanced proliferating cell nuclear antigen, and increased entry of G0/1-arrested cells into S-phase. PTTG binding factor mRNA expression was not altered. EGF-induced Pttg1 expression and cell proliferation was abolished by preincubation of TtT/GF cells with EGFR inhibitors AG1478 and gefitinib. Phosphatidylinositol 3 kinase, protein kinase C, and MAPK, but not c-Jun N-terminal kinase and Janus activating kinase signaling regulated EGF-induced Pttg1, as well as proliferating cell nuclear antigen mRNA expression and entry into S-phase. EGF-induced EGFR and ERK1/2 phosphorylation was followed by rapid MAPK kinase/ERK kinase-dependent activation of Elk-1 and c-Fos. EGF-induced Pttg1 expression peaked at the S-G2 transition and declined thereafter. Pttg1 cell cycle dependency was confirmed by suppression of EGF-induced Pttg1 mRNA by blockade of cells in early S-phase. The results show that PTTG1 and its binding protein PTTG binding factor are expressed in pituitary FS TtT/GF cells. EGFR ligands induce PTTG1 and regulate S-phase, mediated by phosphatidylinositol 3 kinase, protein kinase C, and MAPK pathways. PTTG1 is therefore a target for EGFR-mediated paracrine regulation of pituitary cell growth.
Molecular Endocrinology 01/2007; 20(12):3321-35. · 4.54 Impact Factor
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ABSTRACT: Male mice that are pttg-null develop sexually dimorphic diabetes with hypoinsulinemia secondary to reduced postnatal-cell proliferation and an inability to expand islet cell mass with aging. We therefore examined the effects of sex-steroid manipulation on diabetes development in pttg-/- male mice. Surgical gonadectomy was followed by implantation of 90-day slow-release pellets releasing 17beta-estradiol (0.36 mg/pellet), placebo or dihydrotestosterone (DHT; 12.5 mg/pellet). Mean fasting blood sugars at the end of the study were 414 +/- 54 mg/dl for pttg-/- controls and 371 +/- 14 mg/dl for pttg-/- mice gonadectomized and treated with DHT compared with 124 +/- 40 and 85 +/- 12 mg/dl in gonadectomized pttg-/- males treated with placebo or estradiol, respectively (P < 0.01 compared with control pttg-/-). Gonadectomy with and without estradiol treatment did not increase the very low circulating insulin levels in pttg-null males (fasting insulin 0.44 +/- 0.04 ng/ml in pttg-/- controls, 0.47 +/- 0.07 and 0.4 ng/ml in pttg-/- gonadectomized males treated with placebo or estradiol, respectively). Gonadectomy increased serum adiponectin levels (4.9 +/- 008 microg/ml in pttg-/- controls versus 13 +/- 0.08 and 7.5 +/- 0.6 microg/ml in pttg-/- gonadectomized males treated with placebo or estradiol, respectively; P < 0.001 and P < 0.05), accompanied by increased insulin sensitivity. The results show that gonadectomy delayed, and gonadectomy with additional estradiol treatment prevented, diabetes development in pttg-/- males, possibly through increased insulin sensitivity mediated by elevated serum adiponectin levels. Male-selective effects of disrupted beta-cell proliferation in the absence of pttg are restored by sex-steroid effects on peripheral insulin sensitivity.
Journal of Endocrinology 06/2006; 189(3):519-28. · 3.55 Impact Factor
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S Melmed,
F Casanueva,
F Cavagnini,
P Chanson,
L A Frohman,
R Gaillard,
E Ghigo,
K Ho,
P Jaquet,
D Kleinberg,
S Lamberts,
E Laws,
G Lombardi,
M C Sheppard,
M Thorner,
M L Vance,
J A H Wass,
A Giustina
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ABSTRACT: In November 2003, the Pituitary Society and the European Neuroendocrine Association sponsored a consensus workshop in Seville to address challenging issues in the medical management of acromegaly. Participants comprised 70 endocrinologists and neurosurgeons with international expertise in managing patients with acromegaly. All participants participated in the workshop proceedings, and the final document written by the scientific committee reflects the consensus opinion of the interactive deliberations. The meeting was supported by an unrestricted educational grant from Ipsen. No pharmaceutical representatives participated in the program planning or in the scientific deliberations.
European Journal of Endocrinology 01/2006; 153(6):737-40. · 3.42 Impact Factor
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ABSTRACT: Pituitary tumor initiation and progression are associated with a plethora of genetic imbalances. The role of pituitary trophic status as determinant of neoplastic potential is not clear. The pituitary gland responds to diverse central and peripheral signals by undergoing reversible plastic and functional changes. The resulting hyperplasia/excess hormone production, or involution/hyposecretion in pituitary cells may correlate with the ability to develop pituitary tumors. It is difficult to test this hypothesis, in part due to limitations on the definition of human pituitary cell trophic status and because this organ is not readily accessible for serial histopathological analysis. Therefore, animal models represent the most functional approach to testing this hypothesis. Transgenic mouse models of pituitary tumor transforming gene (PTTG) inactivation or overexpression support the notion that a permissive trophic environment may be required for pituitary tumor formation. Mechanisms underlying changes in pituitary plasticity and their relationship to tumor development may account for the diverse genetic abnormalities observed in pituitary tumors.
Journal of endocrinological investigation 02/2005; 28(11 Suppl International):100-5. · 1.57 Impact Factor
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K Boelaert,
R Yu,
L A Tannahill,
A L Stratford,
F L Khanim,
M C Eggo,
J S Moore,
L S Young,
N J L Gittoes,
J A Franklyn, S Melmed,
C J McCabe
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ABSTRACT: Human pituitary tumor-transforming gene (PTTG), known also as securin, is a multifunctional protein implicated in the control of mitosis and the pathogenesis of thyroid, colon, oesophageal and other tumour types. Critical to PTTG function is a C-terminal double PXXP motif, forming a putative SH3-interacting domain and housing the gene's sole reported phosphorylation site. The exact role of phosphorylation and PXXP structure in the modulation of PTTG action in vitro remains poorly understood. We therefore examined the mitotic, transformation, proliferation and transactivation function of the C-terminal PXXP motifs of human PTTG. Live-cell imaging studies using an EGFP-PTTG construct indicated that PTTG's regulation of mitosis is retained regardless of phosphorylation status. Colony-formation assays demonstrated that phosphorylation of PTTG may act as a potent inhibitor of cell transformation. In proliferation assays, NIH-3T3 cells stable transfected and overexpressing mutations preventing PTTG phosphorylation (Phos-) showed significantly increased [3H]thymidine incorporation compared with WT, whereas mutants mimicking constitutive phosphorylation of PTTG (Phos+) exhibited reduced cell proliferation. We demonstrated that PTTG transactivation of FGF-2 in primary thyroid and PTTG-null cell lines was not affected by PTTG phosphorylation but was prevented by a mutant disrupting the PXXP motifs (SH3-). Taken together, our data suggest that PXXP structure and phosphorylation are likely to exert independent and critical influences upon PTTG's diverse actions in vitro.
Journal of Molecular Endocrinology 01/2005; 33(3):663-77. · 3.48 Impact Factor
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A Giustina,
F F Casanueva,
F Cavagnini,
P Chanson,
D Clemmons,
L A Frohman,
R Gaillard,
K Ho,
P Jaquet,
D L Kleinberg,
S W J Lamberts,
G Lombardi,
M Sheppard,
C J Strasburger,
M L Vance,
J A H Wass, S Melmed
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ABSTRACT: The Pituitary Society in conjunction with the European Neuroendocrine Association held a consensus workshop to develop guidelines for diagnosis and treatment of the co-morbid complications of acromegaly. Fifty nine pituitary specialists (endocrinologists, neurosurgeons and cardiologists) assessed the current published literature on acromegaly complications in light of recent advances in maintaining tight therapeutic control of GH hypersecretion. The impact of elevated GH levels on cardiovascular disease, hypertension, diabetes, sleep apnea, colon polyps, bone disease, reproductive disorders, and neuropsychologic complications were considered. Guidelines are proposed for effective management of these complications in the context of overall acromegaly control. When appropriate, requirements for prospective evidence-based studies and surveillance database development are enunciated. Effective management of co-morbid acromegaly complications will lead to improved morbidity and mortality in acromegaly.
Journal of endocrinological investigation 01/2004; 26(12):1242-7. · 1.57 Impact Factor
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S Melmed,
F F Casanueva,
F Cavagnini,
P Chanson,
L Frohman,
A Grossman,
K Ho,
D Kleinberg,
S Lamberts,
E Laws,
G Lombardi,
M L Vance,
K Von Werder,
J Wass,
A Giustina
Journal of Clinical Endocrinology & Metabolism 10/2002; 87(9):4054-8. · 6.50 Impact Factor
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ABSTRACT: Proteasome inhibitors induce apoptosis in some malignant cells, and we show here that these inhibitors induce apoptosis in rat pituitary MMQ and GH3 tumor cells but not in normal pituitary cells. Three proteasome inhibitors, PSI, MG-132, and lactacystin, but not the calpain inhibitor, ALLM, dose- and time-dependently caused apoptosis in these cells, and 10 microM PSI caused apoptosis in 70% of MMQ cells and in 25% of GH3 cells within 24 h. A lower PSI dose (10 nM) inhibited GH3 cell growth without causing significant apoptosis or affecting prolactin secretion. Primary rat pituitary cells were resistant to both PSI and MG-132 and did not undergo apoptosis. In MMQ cells, DNA synthesis was slowed (approximately 30%) after 6 h of 10 microM PSI treatment and a partial cell cycle block at G2/M was evident after 8 h. Colorimetric caspase substrate assay and Western blotting of caspase substrates showed that caspases 2 and 3 are activated by PSI while caspases 6 and 8 remained inactive. A broad-range caspase inhibitor, caspase inhibitor III, prevented apoptosis induced by PSI. The results show that proteasome inhibitors induce apoptosis in rat pituitary tumor cells by specific caspase activation. This novel group of drugs may potentially be used in treatment of aggressive pituitary tumors, especially as their action appears relative for tumor cells.
Journal of Endocrinology 10/2002; 174(3):379-86. · 3.55 Impact Factor
