title: Expression of p18(INK4C) is down-regulated in human pituitary adenomas.
abstract: Cyclin-dependent kinase inhibitors represented by the INK4 family comprising p16(INK4A), p15(INK4B), p18(INK4C), and p19(INK4D) are regulators of the cell cycle shown to be aberrant in many types of cancer. Mice lacking p18(Ink4c) exhibit a series of phenotypes including the development of widespread organomegaly and pituitary adenomas. The objective of our study is to examine the role of p18(INK4C) in the pathogenesis of human pituitary tumors. The protein and mRNA levels of p18(INK4C) were examined by immunohistochemistry and real-time reverse transcription-polymerase chain reaction, respectively. The methylation status of the p18(INK4C) gene promoter and somatic mutations of the p18(INK4C) gene were also investigated. p18(INK4C) protein expression was lost or significantly reduced in 64% of pituitary adenomas compared with levels in normal pituitary glands. p18(INK4C) mRNA levels were low in all ACTH adenomas and non-functioning (NF)-FSH and in 42%, 70% and 66% of GH, PRL, and subtype 3 adenomas, respectively. p18(INK4C) mRNA levels were significantly associated with p18(INK4C) protein levels. Neither methylated promoters in pituitary adenomas, except in one NF-FSH adenoma, nor somatic mutations of the p18(INK4C) gene in any pituitary adenomas were detected. The down-regulation of p18(INK4C) expression may contribute to the tumorigenesis of pituitary adenomas.
authors.affiliation: Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: M Golam
authors.initials: MG
authors.lastname: Hossain
authors.forename: Takeo
authors.initials: T
authors.lastname: Iwata
authors.forename: Noriko
authors.initials: N
authors.lastname: Mizusawa
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.forename: Shahidan Wan Nazatul
authors.initials: SW
authors.lastname: Shima
authors.forename: Toru
authors.initials: T
authors.lastname: Okutsu
authors.forename: Shozo
authors.initials: S
authors.lastname: Yamada
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sano
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yoshimoto
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D050763:Cyclin-Dependent Kinase Inhibitor p18; D012333:RNA, Messenger