scholarly journals Reduced expression levels of the cell-cycle inhibitor p27Kip1 in human pituitary adenomas

1999 ◽  
pp. 250-255 ◽  
Author(s):  
CM Bamberger ◽  
M Fehn ◽  
AM Bamberger ◽  
DK Ludecke ◽  
FU Beil ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pituitary Adenomas ◽  
Anterior Pituitary ◽  
Cellular Proliferation ◽  
Cell Types ◽  
Null Cell ◽  
Human Pituitary ◽  
Expression Levels ◽  
Cell Cycle Inhibitor ◽  
Null Cell Adenomas

The molecular mechanisms leading to increased cellular proliferation rates and, thus, tumor formation in the anterior pituitary gland are poorly understood. The cyclin-dependent kinase inhibitor p27Kip1 is a key molecule regulating the G1 phase of the cell cycle in many cell types. Furthermore, it was shown that p27 knock-out mice develop pro-opiomelanocortin-positive pituitary tumors. In an effort to clarify the role of p27 in the normal and tumorous human pituitary, we studied the expression of p27 by immunohistochemistry, using a highly specific mouse monoclonal anti-human p27 antibody. Normal pituitaries and 54 pituitary adenomas (twelve somatotrope adenomas, nine prolactinomas, twelve corticotrope adenomas, three TSH-producing tumors, six gonadotrope adenomas, six null cell adenomas, and six oncocytomas) were analyzed. p27 expression was determined semiquantitatively with regard to both the percentage of positive cells and the intensity of the staining. Normal human pituitaries showed strong expression of p27 in most nuclei. In contrast, the levels of p27 were reduced in the majority of the tumors analyzed. Twenty-two tumors (six somatotrope adenomas, five prolactinomas, four corticotrope adenomas, two TSH-producing tumors, two gonadotrope adenomas, and three null cell adenomas) were completely p27-negative. In 18 tumors, p27 expression was found in < or = 10% of the cells. In the other ten tumors, 11-80% of the cells were p27-positive. In summary, we were able to demonstrate reduced expression levels of the cell-cycle inhibitor p27 in tumors derived from all pituitary cell types. Our data indicate that p27 may be an important regulator of cellular proliferation in the anterior pituitary, the underexpression of which could play a role in pituitary tumorigenesis.

scholarly journals Clinically Non-Functioning Human Pituitary Adenomas

1992 ◽  
Vol 19 (2) ◽  
pp. 228-235 ◽  
Author(s):  
Sylvia L. Asa ◽  
Kalman Kovacs
Keyword(s):  
Pituitary Adenomas ◽  
Cell Types ◽  
Null Cell ◽  
Human Pituitary ◽  
Endocrine Activity ◽  
Hormone Synthesis ◽  
A Subunit ◽  
Null Cell Adenomas

ABSTRACT:Clinically non-functioning pituitary adenomas are morphologically classified into two groups, those which have hormone immunoreactivity and ultrastructural features of known adenohypophysial cell types but are clinically silent, and those composed of cells that do not resemble nontumorous adenohypophysial cell types. Among the fomer are the silent somatotroph adenomas, silent corticotroph adenomas and silent gonadotroph adenomas; the latter include the silent type III adenomas, null cell adenomas and oncocytomas. We review their histological, immunohistochemical and ultrastructural features, the results of in situ hybridization to determine hormone synthesis by these tumors and data obtained from tissue culture characterizing their hormone release in vitro. Non-functioning adenomas represent a heterogeneous group. The discrepancies between morphology, immunoreactivity and lack of endocrine activity of silent adenomas are not clear. Oncocytomas are variants of null cell adenomas. We suggest that null cell adenomas and oncocytomas originate in uncommitted pluripotent precursor cells capable of undergoing multidirectional differentiation. The progenitor cells differentiate most frequently toward FSH / a-subunit producing cells; the mechanism of preferential differentiation is obscure.

Pit-1/GHF-1 expression in pituitary adenomas: further analogy between human adenomas and rat SMtTW tumours

1993 ◽  
Vol 11 (2) ◽  
pp. 129-139 ◽  
Author(s):  
M Delhase ◽  
P Vergani ◽  
A Malur ◽  
B Velkeniers ◽  
E Teugels ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pituitary Adenomas ◽  
Anterior Pituitary ◽  
Cell Types ◽  
Cell Type ◽  
Human Pituitary ◽  
Normal Human ◽  
Cell Commitment

ABSTRACT Adenomas can develop from each cell type of the anterior pituitary. In the normal pituitary, three of these cell types, the GH-, prolactin- and TSH-secreting cells, express the transcription factor Pit-1/GHF-1 which is responsible for prolactin and GH (and probably TSH) cell commitment, differentiation, probably proliferation and gene expression. We have analysed the expression of Pit-1/GHF-1 in a panel of human pituitary adenomas. All GH-, prolactin- and TSH-expressing adenomas studied expressed the Pit-1/GHF-1 factor, as demonstrated by in-situ hybridization and immunocytochemistry. The expression was higher in adenomas than in normal human pituitary. In contrast, ACTH- and LH—FSH-secreting and non-secreting adenomas were negative. Seven transplants of the spontaneous rat prolactinoma SMtTW were also investigated and all were found to be positive. This further stresses the analogy between these tumours and human prolactinomas. Taken together, the data confirm that Pit-1/GHF-1 expression is restricted to GH-, prolactin- and TSH-expressing cells, and the increased expression in adenomas is compatible with a role of Pit-1/GHF-1 in cell proliferation.

scholarly journals Thyrotrophin receptor protein expression in normal and adenomatous human pituitary

2000 ◽  
Vol 167 (1) ◽  
pp. 7-13 ◽  
Author(s):  
M Theodoropoulou ◽  
T Arzberger ◽  
Y Gruebler ◽  
Z Korali ◽  
P Mortini ◽  
...  
Keyword(s):  
Protein Expression ◽  
Pituitary Adenomas ◽  
Anterior Pituitary ◽  
Preliminary Evidence ◽  
Positive Control ◽  
Negative Control ◽  
Receptor Protein ◽  
Human Pituitary ◽  
Thyrotrophin Releasing Hormone ◽  
Regulatory Pathways

Thyrotrophin (TSH) synthesis and secretion is under the positive control of thyrotrophin releasing hormone and under the negative control of the thyroid hormones. However, it is hypothesised that TSH has a direct effect on the regulation of its own synthesis through an intrapituitary loop mediated by pituitary TSH receptors (TSH-R). The aim of this investigation was to study the expression of TSH-R in normal human pituitary at mRNA and protein levels, and to compare the pattern of protein expression between different pituitary adenomas. Using RT-PCR we were able to detect TSH-R mRNA in the normal pituitary, and immunohistochemical studies showed TSH-R protein expression in distinct areas of the anterior pituitary. Double immunostaining with antibodies against each of the intrapituitary hormones and S100 revealed that TSH-R protein is present in thyrotrophs and folliculostellate cells. Examination of 58 pituitary adenomas, including two clinically active and two clinically inactive thyrotroph adenomas, revealed TSH-R immunopositivity in only the two clinically inactive thyrotroph adenomas. This study shows, for the first time, the presence of TSH-R protein in the normal anterior pituitary and in a subset of thyrotroph adenomas. The expression of TSH-R in the thyrotroph and folliculostellate cell subpopulations provides preliminary evidence of a role for TSH in autocrine and paracrine regulatory pathways within the anterior pituitary gland.

scholarly journals miR-26a Plays an Important Role in Cell Cycle Regulation in ACTH-Secreting Pituitary Adenomas by Modulating Protein Kinase Cδ

Endocrinology ◽  
2013 ◽  
Vol 154 (5) ◽  
pp. 1690-1700 ◽  
Author(s):  
Erica Gentilin ◽  
Federico Tagliati ◽  
Carlo Filieri ◽  
Daniela Molè ◽  
Mariella Minoia ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pituitary Adenoma ◽  
Protein Kinase ◽  
Pituitary Adenomas ◽  
Viable Cell Number ◽  
Pituitary Cells ◽  
Human Pituitary ◽  
Human Pituitary Adenoma ◽  
Acth Secreting ◽  
Protein Kinase Cδ

Abstract The functional aftermath of microRNA (miRNA) dysregulation in ACTH-secreting pituitary adenomas has not been demonstrated. miRNAs represent diagnostic and prognostic biomarkers as well as putative therapeutic targets; their investigation may shed light on the mechanisms that underpin pituitary adenoma development and progression. Drugs interacting with such pathways may help in achieving disease control also in the settings of ACTH-secreting pituitary adenomas. We investigated the expression of 10 miRNAs among those that were found as most dysregulated in human pituitary adenoma tissues in the settings of a murine ACTH-secreting pituitary adenoma cell line, AtT20/D16v-F2. The selected miRNAs to be submitted to further investigation in AtT20/D16v-F2 cells represent an expression panel including 5 up-regulated and 5 down-regulated miRNAs. Among these, we selected the most dysregulated mouse miRNA and searched for miRNA targets and their biological function. We found that AtT20/D16v-F2 cells have a specific miRNA expression profile and that miR-26a is the most dysregulated miRNA. The latter is overexpressed in human pituitary adenomas and can control viable cell number in the in vitro model without involving caspase 3/7-mediated apoptosis. We demonstrated that protein kinase Cδ (PRKCD) is a direct target of miR-26a and that miR26a inhibition delays the cell cycle in G1 phase. This effect involves down-regulation of cyclin E and cyclin A expression via PRKCD modulation. miR-26a and related pathways, such as PRKCD, play an important role in cell cycle control of ACTH pituitary cells, opening new therapeutic possibilities for the treatment of persistent/recurrent Cushing's disease.

scholarly journals Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division

2018 ◽  
Author(s):  
Evgeny Zatulovskiy ◽  
Daniel F. Berenson ◽  
Benjamin R. Topacio ◽  
Jan M. Skotheim
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Growth ◽  
Cell Size ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Inverse Correlation ◽  
Cell Types ◽  
Similar Amount ◽  
Cell Cycle Inhibitor

Cell size is fundamental to function in different cell types across the human body because it sets the scale of organelle structures, biosynthesis, and surface transport1,2. Tiny erythrocytes squeeze through capillaries to transport oxygen, while the million-fold larger oocyte divides without growth to form the ~100 cell pre-implantation embryo. Despite the vast size range across cell types, cells of a given type are typically uniform in size likely because cells are able to accurately couple cell growth to division3–6. While some genes whose disruption in mammalian cells affects cell size have been identified, the molecular mechanisms through which cell growth drives cell division have remained elusive7–12. Here, we show that cell growth acts to dilute the cell cycle inhibitor Rb to drive cell cycle progression from G1 to S phase in human cells. In contrast, other G1/S regulators remained at nearly constant concentration. Rb is a stable protein that is synthesized during S and G2 phases in an amount that is independent of cell size. Equal partitioning to daughter cells of chromatin bound Rb then ensures that all cells at birth inherit a similar amount of Rb protein. RB overexpression increased cell size in tissue culture and a mouse cancer model, while RB deletion decreased cell size and removed the inverse correlation between cell size at birth and the duration of G1 phase. Thus, Rb-dilution by cell growth in G1 provides a long-sought cell autonomous molecular mechanism for cell size homeostasis.

scholarly journals c-Myc Regulates Cyclin D-Cdk4 and -Cdk6 Activity but Affects Cell Cycle Progression at Multiple Independent Points

1999 ◽  
Vol 19 (7) ◽  
pp. 4672-4683 ◽  
Author(s):  
Maria K. Mateyak ◽  
Alvaro J. Obaya ◽  
John M. Sedivy
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Growth Defect ◽  
Cyclin Dependent Kinase ◽  
Null Cell ◽  
Cycle Progression ◽  
Fold Reduction ◽  
Line Loss

ABSTRACT c-myc is a cellular proto-oncogene associated with a variety of human cancers and is strongly implicated in the control of cellular proliferation, programmed cell death, and differentiation. We have previously reported the first isolation of a c-myc-null cell line. Loss of c-Myc causes a profound growth defect manifested by the lengthening of both the G1and G2 phases of the cell cycle. To gain a clearer understanding of the role of c-Myc in cellular proliferation, we have performed a comprehensive analysis of the components that regulate cell cycle progression. The largest defect observed in c-myc −/− cells is a 12-fold reduction in the activity of cyclin D1-Cdk4 and -Cdk6 complexes during the G0-to-S transition. Downstream events, such as activation of cyclin E-Cdk2 and cyclin A-Cdk2 complexes, are delayed and reduced in magnitude. However, it is clear that c-Myc affects the cell cycle at multiple independent points, because restoration of the Cdk4 and -6 defect does not significantly increase growth rate. In exponentially cycling cells the absence of c-Myc reduces coordinately the activities of all cyclin–cyclin-dependent kinase complexes. An analysis of cyclin-dependent kinase complex regulators revealed increased expression of p27 KIP1 and decreased expression of Cdk7 in c-myc −/− cells. We propose that c-Myc functions as a crucial link in the coordinate adjustment of growth rate to environmental conditions.

Null cell adenomas, oncocytomas, and gonadotroph adenomas of the human pituitary: An immunocytochemical and ultrastructural anafysis of 300 cases

1993 ◽  
Vol 4 (1) ◽  
pp. 20-27 ◽  
Author(s):  
George Kontogeorgos ◽  
Kalman Kovacs ◽  
Eva Horvath ◽  
Bernd W. Scheithauer
Keyword(s):  
Null Cell ◽  
Human Pituitary ◽  
Null Cell Adenomas

scholarly journals Line Scan Raman Microspectroscopy for Label-Free Diagnosis of Human Pituitary Biopsies

Molecules ◽  
2019 ◽  
Vol 24 (19) ◽  
pp. 3577 ◽  
Author(s):  
Daniela Bovenkamp ◽  
Alexander Micko ◽  
Jeremias Püls ◽  
Fabian Placzek ◽  
Romana Höftberger ◽  
...  
Keyword(s):  
Pituitary Gland ◽  
Pituitary Adenomas ◽  
Nearest Neighbor ◽  
Principal Component ◽  
Raman Microspectroscopy ◽  
Label Free ◽  
K Nearest Neighbor ◽  
Null Cell ◽  
Human Pituitary ◽  
Line Scan

Pituitary adenomas are neoplasia of the anterior pituitary gland and can be subdivided into hormone-producing tumors (lactotroph, corticotroph, gonadotroph, somatotroph, thyreotroph or plurihormonal) and hormone-inactive tumors (silent or null cell adenomas) based on their hormonal status. We therefore developed a line scan Raman microspectroscopy (LSRM) system to detect, discriminate and hyperspectrally visualize pituitary gland from pituitary adenomas based on molecular differences. By applying principal component analysis followed by a k-nearest neighbor algorithm, specific hormone states were identified and a clear discrimination between pituitary gland and various adenoma subtypes was achieved. The classifier yielded an accuracy of 95% for gland tissue and 84–99% for adenoma subtypes. With an overall accuracy of 92%, our LSRM system has proven its potential to differentiate pituitary gland from pituitary adenomas. LSRM images based on the presence of specific Raman bands were created, and such images provided additional insight into the spatial distribution of particular molecular compounds. Pathological states could be molecularly differentiated and characterized with texture analysis evaluating Grey Level Cooccurrence Matrices for each LSRM image, as well as correlation coefficients between LSRM images.

Expression of polo-like kinase (PLK) in the mouse placenta and ovary

1999 ◽  
Vol 11 (1) ◽  
pp. 31 ◽  
Author(s):  
Noriyuki Takai ◽  
Jun Yoshimatsu ◽  
Yoshihiro Nishida ◽  
Isao Miyakawa ◽  
Ryoji Hamanaka ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cellular Proliferation ◽  
Cultured Cells ◽  
Embryo Implantation ◽  
Cell Types ◽  
Nuclear Antigen ◽  
Ovarian Stroma ◽  
Mouse Placenta ◽  
Trophoblastic Tissue

The polo-like kinase (PLK) is a mammalian serine/threonine kinase involved in cell cycle regulation. Much evidence for the role of PLK in the cell cycle has come from studies of cultured cells; however, little is known about its function or even expression in vivo . The present study examined the features of PLK expression in the mouse placenta and ovary. Immunohistochemical studies showed that PLK is highly expressed in the basement membrane of the endometrial gland, in some endothelial cells, in endometrium after embryo implantation, in trophoblastic tissue invading the decidua, in the ovarian stroma and in some lutein bodies. In contrast, PLK was not detectable by immunohistochemistry in endometrial stroma before decidualization, in decidua, in trophoblastic tissue not invading the decidua or in ovarian follicles. PLK expression seemed to be correlated with the expression of proliferation cellular nuclear antigen (PCNA) in many placental and ovarian cells, reflecting a role in cellular proliferation. Nevertheless, in ovarian stroma and lutein bodies where PCNA was not expressed, PLK was strongly expressed. This finding indicates that PLK may have some post mitotic functions in certain specialized cell types.

Sign in / Sign up

Export Citation Format

Share Document