scholarly journals Identification of Growth Arrest and DNA-Damage-Inducible Gene β (GADD45β) as a Novel Tumor Suppressor in Pituitary Gonadotrope Tumors

Endocrinology ◽  
2011 ◽  
Vol 152 (10) ◽  
pp. 3603-3613 ◽  
Author(s):  
Katherine A. Michaelis ◽  
Aaron J. Knox ◽  
Mei Xu ◽  
Katja Kiseljak-Vassiliades ◽  
Michael G. Edwards ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Pituitary Tumor ◽  
Growth Arrest ◽  
Pituitary Tumors ◽  
Bioinformatic Analysis ◽  
Soft Agar ◽  
Null Cell ◽  
Human Pituitary ◽  
Downstream Effectors

Gonadotrope and null cell pituitary tumors cause significant morbidity, often presenting with signs of hypogonadism together with visual disturbances due to mass effects. Surgery and radiation are the only therapeutic options to date. To identify dysregulated genes and pathways that may play a role in tumorigenesis and/or progression, molecular profiling was performed on 14 gonadotrope tumors, with nine normal human pituitaries obtained at autopsy serving as controls. Bioinformatic analysis identified putative downstream effectors of tumor protein 53 (p53) that were consistently repressed in gonadotrope pituitary tumors, including RPRM, P21, and PMAIP1, with concomitant inhibition of the upstream p53 regulator, PLAGL1(Zac1). Further analysis of the growth arrest and DNA damage-inducible (GADD45) family revealed no change in the p53 target, GADD45α, but identified repression of GADD45β in pituitary tumors in addition to the previously reported inhibition of GADD45γ. Overexpression of GADD45β in LβT2 mouse gonadotrope cells blocked tumor cell proliferation and increased rates of apoptosis in response to growth factor withdrawal. Stable gonadotrope cell transfectants expressing increased GADD45β showed decreased colony formation in soft agar, confirming its normal role as a tumor suppressor. Unlike previous studies of GADD45γ in pituitary tumors and α and β in other tumors, bisulfite sequencing showed no evidence of hypermethylation of the GADD45β promoter in human pituitary tumor samples to explain the repression of its expression. Thus, GADD45β is a novel pituitary tumor suppressor whose reexpression blocks proliferation, survival, and tumorigenesis. Together these studies identify new targets and mechanisms to explore in pituitary tumor initiation and progression.

scholarly journals Reprimo (RPRM) Is a Novel Tumor Suppressor in Pituitary Tumors and Regulates Survival, Proliferation, and Tumorigenicity

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 2963-2973 ◽  
Author(s):  
Mei Xu ◽  
Aaron J. Knox ◽  
Katherine A. Michaelis ◽  
Katja Kiseljak-Vassiliades ◽  
Bette K. Kleinschmidt-DeMasters ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tumor Suppressor ◽  
Cellular Stress ◽  
Pituitary Tumors ◽  
Tumor Formation ◽  
Gh3 Cells ◽  
Pituitary Cells ◽  
Null Cell ◽  
Human Pituitary ◽  
Protein Levels

Reprimo (RPRM), initially identified as a downstream effector of p53-induced cell cycle arrest at G2/M, is a putative tumor suppressor silenced in some types of cancer. In microarrays, the RPRM transcript was repressed 26-fold in gonadotrope (null cell) human pituitary tumors compared with normal pituitary but in the absence of changes in p53. Inhibition of RPRM mRNA was confirmed by RT-PCR in all gonadotrope tumors, most GH samples, and variably in other tumor types. Human pituitary tumors showed no evidence of abnormal promoter hypermethylation as a mechanism of RPRM repression. RPRM stable expression in gonadotrope (LβT2) and GH (GH3) pituitary cells resulted in decreased rates of cell proliferation by 55 and 30%, respectively; however, RPRM reexpression did not alter G2/M transition. In addition, RPRM increased rates of apoptosis in response to growth factor deprivation as assessed by caspase-3 cleavage and nuclear condensation. Clonagenic assays showed a 5.3- and 3.7-fold suppression of colony growth in RPRM-overexpressing LβT2 and GH3 cells, respectively, supporting its role as a tumor suppressor. In cells stably expressing RPRM mRNA, protein levels were actively suppressed due to rapid degradation through ubiquitination and proteasomal targeting. Growth factor withdrawal, as a model of cellular stress, stabilized RPRM protein levels. Together these data suggest that RPRM is transiently up-regulated at a posttranscriptional level in times of cellular stress to restrict cell survival, proliferation, and tumor formation. When RPRM is silenced as in human pituitary tumors, unrestrained growth and tumor progression may occur.

scholarly journals E2F1 Induces Pituitary Tumor Transforming Gene (PTTG1) Expression in Human Pituitary Tumors

2009 ◽  
Vol 23 (12) ◽  
pp. 2000-2012 ◽  
Author(s):  
Cuiqi Zhou ◽  
Kolja Wawrowsky ◽  
Serguei Bannykh ◽  
Shiri Gutman ◽  
Shlomo Melmed
Keyword(s):  
Pituitary Tumor ◽  
Pituitary Tumors ◽  
Human Pituitary ◽  
Pituitary Tumor Transforming Gene ◽  
Transforming Gene

scholarly journals Mutation and expression analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in pituitary tumors

1998 ◽  
Vol 157 (2) ◽  
pp. 337-341 ◽  
Author(s):  
S Takeuchi ◽  
HP Koeffler ◽  
DR Hinton ◽  
I Miyoshi ◽  
S Melmed ◽  
...  
Keyword(s):  
Pituitary Tumor ◽  
Structural Changes ◽  
Kinase Inhibitor ◽  
Pituitary Tumors ◽  
Cyclin Dependent Kinase ◽  
Coding Region ◽  
Complex Activity ◽  
Human Pituitary ◽  
Protein Levels ◽  
P27 Kip1

By regulating cyclin-cyclin-dependent kinase (CDK) complex activity, individual CDK inhibitors (CDKIs) are potential tumor suppressors. One of the CDKIs, p27/Kip1, binds to a variety of CDK-cyclin complexes. A link between loss of p27/Kip1 function and development of pituitary tumors was suggested by the formation of pituitary tumors in almost all mice with germline deletion of the p27/Kip1 gene. However, genetic aberrations in the p27/Kip1 locus have not been analyzed in human pituitary tumors. We investigated eighteen non-functioning and GH-secreting pituitary tumor samples for p27/Kip1 mutations by single-strand conformational polymorphism (SSCP) following PCR. We found five abnormally migrating samples on the PCR-SSCP analysis. The sequence of these samples revealed a polymorphism of codon 109 (Val-->Gly), which has been previously described. No other structural changes of p27/Kip1 were found in these pituitary tumors within the coding region. In addition, no difference in p27/Kip1 protein levels in pituitary tumor tissues compared with normal pituitary tissues was demonstrated by immunostaining. These data suggest that both p27/Kip1 mutations and decreases in p27/Kip1 protein levels are infrequent in the development of pituitary tumors.

scholarly journals F-box protein FBXO31 directs degradation of MDM2 to facilitate p53-mediated growth arrest following genotoxic stress

2015 ◽  
Vol 112 (28) ◽  
pp. 8632-8637 ◽  
Author(s):  
Sunil K. Malonia ◽  
Parul Dutta ◽  
Manas Kumar Santra ◽  
Michael R. Green
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Critical Role ◽  
Growth Arrest ◽  
Genotoxic Stress ◽  
26S Proteasome ◽  
Negative Regulator ◽  
Induce Cell Cycle Arrest ◽  
Cycle Arrest ◽  
F Box Protein

The tumor suppressor p53 plays a critical role in maintaining genomic stability. In response to genotoxic stress, p53 levels increase and induce cell-cycle arrest, senescence, or apoptosis, thereby preventing replication of damaged DNA. In unstressed cells, p53 is maintained at a low level. The major negative regulator of p53 is MDM2, an E3 ubiquitin ligase that directly interacts with p53 and promotes its polyubiquitination, leading to the subsequent destruction of p53 by the 26S proteasome. Following DNA damage, MDM2 is degraded rapidly, resulting in increased p53 stability. Because of the important role of MDM2 in modulating p53 function, it is critical to understand how MDM2 levels are regulated. Here we show that the F-box protein FBXO31, a candidate tumor suppressor encoded in 16q24.3 for which there is loss of heterozygosity in various solid tumors, is responsible for promoting MDM2 degradation. Following genotoxic stress, FBXO31 is phosphorylated by the DNA damage serine/threonine kinase ATM, resulting in increased levels of FBXO31. FBXO31 then interacts with and directs the degradation of MDM2, which is dependent on phosphorylation of MDM2 by ATM. FBXO31-mediated loss of MDM2 leads to elevated levels of p53, resulting in growth arrest. In cells depleted of FBXO31, MDM2 is not degraded and p53 levels do not increase following genotoxic stress. Thus, FBXO31 is essential for the classic robust increase in p53 levels following DNA damage.

scholarly journals Overexpression of Wild-Type Activin Receptor Alk4-1 Restores Activin Antiproliferative Effects in Human Pituitary Tumor Cells

2002 ◽  
Vol 87 (10) ◽  
pp. 4741-4746 ◽  
Author(s):  
Daniel C. Danila ◽  
Xun Zhang ◽  
Yunli Zhou ◽  
Jaafar N. Sleiman Haidar ◽  
Anne Klibanski
Keyword(s):  
Cell Proliferation ◽  
Cell Line ◽  
Pituitary Tumor ◽  
Pituitary Tumors ◽  
Type I ◽  
Wild Type ◽  
Human Pituitary ◽  
Activin Signaling ◽  
Hp75 Cells ◽  
Human Pituitary Tumor

Activin is a member of the TGFβ family of cytokines involved in the control of cell proliferation. We have previously shown that the majority of clinically nonfunctioning pituitary tumors do not respond to activin-induced growth suppression. Human pituitary tumors specifically express alternatively spliced activin type I receptor Alk4 mRNAs, producing C-terminus truncated isoforms designated Alk4-2, 4-3, and 4-4. However, it is not known whether these truncated activin receptors suppress activin effects on cell proliferation in human pituitary cells. Therefore, we investigated activin signaling in a human pituitary tumor cell line, HP75, derived from a clinically nonfunctioning pituitary tumor. HP75 cells express activin A mRNA and secrete activin A, as measured by ELISA and a functional bioassay. TGFβ administration decreases the proliferation of HP75 cells, suggesting that the signaling pathway shared by TGFβ and activin is functional in this cell line. However, activin neither inhibits cell proliferation nor stimulates reporter gene expression in HP75 cells, indicating that activin signaling is specifically blocked at the receptor level. HP75 cells express all truncated activin type I receptor Alk4 isoforms, as determined by RT-PCR. Because truncated Alk4 receptor isoforms inhibit activin signaling by competing with the wild-type receptor for binding to activin type II receptors, we hypothesized that overexpression of wild-type activin type I receptor will restore activin signaling. In HP75 cells, cotransfection of the wild-type activin type I receptor Alk4-1 expression vector increases activin-responsive reporter activity. Furthermore, transfection with wild-type activin receptor type I results in activin-mediated suppression of cell proliferation. These data indicate that truncated Alk4 isoforms interfere with activin signaling pathways and thereby may contribute to uncontrolled cell growth. Overexpression of the wild-type Alk4-1 receptor restores responsiveness to activin in human pituitary tumor-derived cells.

Inhibitory Action of Bromocriptine and Tamoxifen on the Growth of Human Pituitary Tumors in Soft Agar*

1983 ◽  
Vol 57 (5) ◽  
pp. 986-992 ◽  
Author(s):  
BAHA’UDDIN M. ARAFAH ◽  
BETH L. WILHITE ◽  
JOHN RAINIERI ◽  
JERALD S. BRODKEY ◽  
OLOF H. PEARSON
Keyword(s):  
Inhibitory Action ◽  
Pituitary Tumors ◽  
Soft Agar ◽  
Human Pituitary

scholarly journals The HINT1 tumor suppressor regulates both γ-H2AX and ATM in response to DNA damage

2008 ◽  
Vol 183 (2) ◽  
pp. 253-265 ◽  
Author(s):  
Haiyang Li ◽  
Adayabalam S. Balajee ◽  
Tao Su ◽  
Bo Cen ◽  
Tom K. Hei ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Chromosomal Abnormalities ◽  
Cellular Responses ◽  
Suppressor Gene ◽  
Tumor Suppressor Function ◽  
Suppressor Function ◽  
Downstream Effectors ◽  
Induced Apoptosis

Hint1 is a haploinsufficient tumor suppressor gene and the underlying molecular mechanisms for its tumor suppressor function are unknown. In this study we demonstrate that HINT1 participates in ionizing radiation (IR)–induced DNA damage responses. In response to IR, HINT1 is recruited to IR-induced foci (IRIF) and associates with γ-H2AX and ATM. HINT1 deficiency does not affect the formation of γ-H2AX foci; however, it impairs the removal of γ-H2AX foci after DNA damage and this is associated with impaired acetylation of γ-H2AX. HINT1 deficiency also impairs acetylation of ATM and activation of ATM and its downstream effectors, and retards DNA repair, in response to IR. HINT1-deficient cells exhibit resistance to IR-induced apoptosis and several types of chromosomal abnormalities. Our findings suggest that the tumor suppressor function of HINT1 is caused by, at least in part, its normal role in enhancing cellular responses to DNA damage by regulating the functions of both γ-H2AX and ATM.

scholarly journals Angiogenesis in Pituitary Adenomas: Human Studies and New Mutant Mouse Models

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Carolina Cristina ◽  
Guillermina María Luque ◽  
Gianina Demarchi ◽  
Felicitas Lopez Vicchi ◽  
Lautaro Zubeldia-Brenner ◽  
...  
Keyword(s):  
Pituitary Adenomas ◽  
Pituitary Tumor ◽  
Tumor Development ◽  
Pituitary Tumors ◽  
Vascular Supply ◽  
Tumor Burden ◽  
Angiogenic Factor ◽  
Endothelial Cell Proliferation ◽  
Human Pituitary

The role of angiogenesis in pituitary tumor development has been questioned, as pituitary tumors have been usually found to be less vascularized than the normal pituitary tissue. Nevertheless, a significantly higher degree of vasculature has been shown in invasive or macropituitary prolactinomas when compared to noninvasive and microprolactinomas. Many growth factors and their receptors are involved in pituitary tumor development. For example, VEGF, FGF-2, FGFR1, and PTTG, which give a particular vascular phenotype, are modified in human and experimental pituitary adenomas of different histotypes. In particular, vascular endothelial growth factor, VEGF, the central mediator of angiogenesis in endocrine glands, was encountered in experimental and human pituitary tumors at different levels of expression and, in particular, was higher in dopamine agonist resistant prolactinomas. Furthermore, several anti-VEGF techniques lowered tumor burden in human and experimental pituitary adenomas. Therefore, even though the role of angiogenesis in pituitary adenomas is contentious, VEGF, making permeable pituitary endothelia, might contribute to adequate temporal vascular supply and mechanisms other than endothelial cell proliferation. The study of angiogenic factor expression in aggressive prolactinomas with resistance to dopamine agonists will yield important data in the search of therapeutical alternatives.

scholarly journals The Microenvironment of Pituitary Tumors—Biological and Therapeutic Implications

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1605 ◽  
Author(s):  
Mirela Diana Ilie ◽  
Alexandre Vasiljevic ◽  
Gérald Raverot ◽  
Philippe Bertolino
Keyword(s):  
Extracellular Matrix ◽  
Therapeutic Target ◽  
Pituitary Tumor ◽  
Current Knowledge ◽  
Tumor Biology ◽  
Pituitary Tumors ◽  
Human Pituitary ◽  
Therapeutic Implications ◽  
Extracellular Matrix Components

The tumor microenvironment (TME) includes resident and infiltrative non-tumor cells, as well as blood and lymph vessels, extracellular matrix molecules, and numerous soluble factors, such as cytokines and chemokines. While the TME is now considered to be a prognostic tool and a therapeutic target for many cancers, little is known about its composition in pituitary tumors. This review summarizes our current knowledge of the TME within pituitary tumors and the strong interest in TME as a therapeutic target. While we cover the importance of angiogenesis and immune infiltrating cells, we also address the role of the elusive folliculostellate cells, the emerging literature on pituitary tumor-associated fibroblasts, and the contribution of extracellular matrix components in these tumors. The cases of human pituitary tumors treated with TME-targeting therapies are reviewed and emerging concepts of vascular normalization and combined therapies are presented. Together, this snapshot overview of the current literature pinpoints not only the underestimated role of TME components in pituitary tumor biology, but also the major promise it may offer for both prognosis and targeted therapeutics.

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