Low expression of the cell cycle inhibitor p27Kip1 in normal corticotroph cells, corticotroph tumors, and malignant pituitary tumors.
Kulbir Lidhar,Márta Korbonits,Suzanne Jordan,Zamira Khalimova,Gregory Kaltsas,Xin Lu,Richard N. Clayton,Paul J. Jenkins,John P. Monson,G. Michael Besser,David G. Lowe,Ashley B. Grossman +11 more
TLDR
It is concluded that pituitary adenomas show a lower level of p 27 protein expression than the normal cells from which they are derived, with malignant transformation leading to complete loss of p27 immunoreactivity.Abstract:
The cell cycle is regulated by a number of inhibitors, including p27 Kip1 (p27), which belongs to the kip1 family. By binding to the cyclin/cyclin-dependent kinase complexes, it regulates progression of G1 to S phase in the cell cycle. It has been reported that p27 knockout mice develop multiorgan hyperplasia and intermediate lobe pituitary tumors secreting ACTH. Previously, we and others have been unable to show any consistent change in messenger RNA expression or genomic mutations for p27 in human corticotroph adenomas. However, dysregulation at the protein level has been reported in nonendocrine tumors, and we, therefore, investigated the expression of p27 in a range of benign and metastatic pituitary tumors. We studied a total of 107 pituitaries, including normal pituitary (n 5 20), Cushing’s disease (n 5 21), acromegaly (n 5 19), nonfunctioning adenomas (n 5 18), prolactinomas (n 5 7), TSH-omas (n 5 2), FSH-omas (n 5 6), aggressive tumors showing invasiveness and recurrence (n 5 9), and metastatic pituitary carcinomas (n 5 5). Using standard immunohistochemical techniques with a highly specific monoclonal antibody, p27 expression was determined quantitatively as the percentage of cells showing strongly positive, weak, or negative staining. In each sample, ;500 cells were analyzed. We also analyzed normal pituitaries using double-labeling for p27 and each of the pituitary hormones to characterize the expression of p27 in each cell type. p27 was expressed in normal pituitary cells; in tumors expressing GH, prolactin, TSH, and FSH; and in aggressive tumors, but markedly reduced expression of p27 was seen in corticotroph tumors and pituitary carcinomas. In the normal pituitary, somatotroph, lactotroph, and thyrotroph cells showed strong p27 staining, whereas normal corticotroph cells showed a much lower level of p27 staining (P , 0.001). Somatotroph, lactotroph, gonadotroph, and thyrotroph adenomas showed a lower level of p27 expression compared with normal somatotrophs (P 5 0.02), lactotrophs (P 5 0.03), gonadotrophs (P 5 0.01), and thyrotrophs, respectively, whereas the lower level of p27 expression present in normal corticotrophs virtually disappeared in corticotroph adenomas (P 5 0.001). We conclude that pituitary adenomas show a lower level of p27 protein expression than the normal cells from which they are derived, with malignant transformation leading to complete loss of p27 immunoreactivity. Corticotrophs are quite different to other pituitary cell types in terms of p27 immunoreactivity because both normal and tumorous corticotrophs have low p27 staining, and we speculate that this may relate to their inherent control mechanisms. (J Clin Endocrinol Metab 84: 3823‐3830, 1999)read more
Citations
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Journal ArticleDOI
Cushing's syndrome
TL;DR: The current understanding of pathogenesis, clinical features, diagnostic, and differential diagnostic approaches, and diagnostic algorithms and recommendations for management of Cushing's syndrome are reviewed.
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Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors
Thomas A. Milne,Christina M. Hughes,Ricardo V. Lloyd,Zhaohai Yang,Orit Rozenblatt-Rosen,Yali Dou,Robert W. Schnepp,Cynthia Krankel,Virginia A. LiVolsi,Denise Gibbs,Xianxin Hua,Robert G. Roeder,Matthew Meyerson,Jay L. Hess +13 more
TL;DR: It is shown that menin directly regulates expression of the cyclin-dependent kinase inhibitors p27Kip1 and p18Ink4c and plays a central role in menin's activity as a tumor suppressor.
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The pathogenesis of pituitary tumours
Sylvia L. Asa,Shereen Ezzat +1 more
TL;DR: Pituitary tumours are common and show a range of hormonal and proliferative behaviours that provide a model for the study of neoplasia mechanisms, although there are many differences in disease pathogenesis between mice and humans.
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Mechanisms for pituitary tumorigenesis: the plastic pituitary.
TL;DR: The mechanisms underlying hereditary pituitsary hypoplasia, reversible pituitary hyperplasia, excess hormone production, and tumor initiation and promotion associated with normal and abnormal pituitaries differentiation in health and disease are discussed.
Journal ArticleDOI
Diagnosis and Management of Pituitary Carcinomas
Gregory Kaltsas,Panagiotis Nomikos,George Kontogeorgos,Michael Buchfelder,Ashley B. Grossman +4 more
TL;DR: It is believed there will be any real prospect of long-term survival until the development and use of therapies targeted at specific molecular abnormalities are targeted, including various attempts at medical therapy.
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Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals
Kornelia Polyak,Mong Hong Lee,Hediye Erdjument-Bromage,Andrew Koff,James M. Roberts,Paul Tempst,Joan Massagué +6 more
TL;DR: P27 Kip1 as mentioned in this paper is a cyclin-dependent kinase inhibitor implicated in G1 phase arrest by TGFβ and cell-cell contact, and it has been shown to be highly conserved and broadly expressed in human tissues, and its mRNA levels are similar in proliferating and quiescent cells.
Journal ArticleDOI
p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21
Hideo Toyoshima,Tony Hunter +1 more
TL;DR: Using a yeast interaction screen to search for proteins that interact with cyclin D1-Cdk4, this article identified a 27 kDa mouse protein related to the p21 cyclin Cdk inhibitor.
Journal ArticleDOI
p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest.
Kornelia Polyak,Jun-ya Kato,Mark J. Solomon,Charles J. Sherr,Joan Massagué,James M. Roberts,Andrew Koff +6 more
TL;DR: Cyclin D2-Cdk4 complexes bind competitively to and down-regulate the activity of p27 and may thereby act in a pathway that reverses Cdk2 inhibition and enables G1 progression.