Molecular analysis of p21 and p27 genes in human pituitary adenomas

Ikeda, Hidetoshi; Yoshimoto, Takashi; Shida, Naoki

doi:10.1038/bjc.1997.521

Cited by 47 publications

(24 citation statements)

References 18 publications

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“…What could be the mechanisms leading to downregulation of p27 in pituitary cells? Several investigators have analyzed whether mutations in the p27 gene could account for pituitary tumor development, yet no such mutations were detected in pituitary adenomas (32)(33)(34). This is consistent with previous findings in other types of neoplasias, including malignant tumors, in which p27 mutations were highly infrequent (35,36).…”

Section: Discussionsupporting

confidence: 75%

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

Bamberger¹,

Fehn

Bamberger³

et al. 1999

European Journal of Endocrinology

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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 Յ10% 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.

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Section: Discussionsupporting

confidence: 75%

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

Bamberger¹,

Fehn

Bamberger³

et al. 1999

European Journal of Endocrinology

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“…Indeed, p27-null mice develop pituitary intermediate lobe adenomas (Fero et al 1996, Kiyokawa et al 1996, Nakayama et al 1996, and heterozygous p27 C/K mice display pituitary hyperplasia (Fero et al 1998). While human pituitary adenomas only rarely showed somatic CDKN1B mutations, downregulation of p27 is observed frequently in these tumors, especially in corticotropinomas , Ikeda et al 1997, Jin et al 1997, Takeuchi et al 1998. Interest was renewed by the discovery that germline CDKN1B mutations in both the rat MENX and the human MEN4 syndromes are associated with development of pituitary adenomas (Fritz et al 2002, Pellegata et al 2006.…”

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds

Tichomirowa¹,

Lee²,

Barlier³

et al. 2012

Endocrine-Related Cancer

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Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations inAIPaccount only for 15–25% of FIPA families.CDKN1Bmutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations inCDKN1Boccur among a large cohort ofAIPmutation-negative FIPA kindreds. Eighty-eightAIPmutation-negative FIPA families were studied and 124 affected subjects underwent sequencing ofCDKN1B. Functional analysis of putativeCDKN1Bmutations was performed usingin silicoandin vitroapproaches. GermlineCDKN1Banalysis revealed two nucleotide changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T).In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27I119Tshows an abnormal migration pattern by SDS–PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic becauseIn vitroeffects were not seen. In conclusion, two patients had germline sequence changes inCDKN1B, which led to functional alterations in the encoded p27 proteinsin vitro. Such rareCDKN1Bvariants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients makeCDKN1Bsequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role ofCDKN1Bin pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.

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“…Tissues were deparaffinized and DNA extracted as previously described. 16 DNA samples were stored at 4°C before use. One g of DNA was digested with 20 -30 U methylation-sensitive restriction endonuclease Hha I (Toyobo Co., Ltd., Tokyo, Japan) in the buffer supplied by the manufacturer to a final volume of 20 L. The samples were incubated overnight at 30°C, followed by heat inactivation at 94°C for 10 minutes.…”

Section: Dna Extraction and Enzyme Digestionmentioning

confidence: 99%

Clinicopathologic study of 123 cases of prolactin‐secreting pituitary adenomas with special reference to multihormone production and clonality of the adenomas

Ikeda

Yoshimoto

2002

Cancer

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BACKGROUNDProlactinoma is the most invasive type of pituitary adenoma and is generally believed to be well‐differentiated adenoma and to produce only prolactin (PRL). The factors related to the various biologic behaviors occurring in patients of different ages and sexes await clarification. Since different immunophenotypes of adenoma may show different biologic behaviors and responses to medical agents, the authors examined hormone production and tried to clarify the clonality of plurihormonal prolactinoma.METHODSClinicopathologic factors were studied in 123 patients with prolactinomas (40 males and 83 females). The specimens were fixed in either 10% neutral buffered formalin or 70% alcohol and used for light microscopy. Alcohol‐fixed tissue was used to extract DNA from 26 samples obtained from female patients for human androgen receptor gene (HUMARA) assay.RESULTSSixty one cases (50%) were pure prolactinoma and 62 cases (50%) were plurihormonal prolactinoma. Spearman rank correlation analysis revealed a significant relationship between age and serum PRL level (P = 0.0002), age and tumor volume (P < 0.0001), and tumor volume and serum PRL level (P < 0.0001). Multiple regression analysis showed a significant correlation only between tumor volume and serum PRL level. The Mann‐Whitney U test revealed that prolactinomas associated with higher PRL levels, larger adenomas, and higher ages were significantly more invasive to the cavernous sinus and that male patients had significantly higher PRL levels and larger adenomas. The HUMARA assay disclosed that 11 of 13 plurihormonal prolactinomas (85%) were compatible with monoclonal origin.CONCLUSIONSThe current results suggest that not only can various hormones other than PRL be secreted by prolactinoma, but also that most multihormone‐producing prolactinomas are monoclonal in origin. Cancer 2002;95:258–66. © 2002 American Cancer Society.DOI 10.1002/cncr.10676

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Molecular analysis of p21 and p27 genes in human pituitary adenomas

Cited by 47 publications

References 18 publications

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

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

Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds

Clinicopathologic study of 123 cases of prolactin‐secreting pituitary adenomas with special reference to multihormone production and clonality of the adenomas

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