Expression of p18(INK4C) is down-regulated in human pituitary adenomas.

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.

Compressive force inhibits adipogenesis through COX-2-mediated down-regulation of PPARgamma2 and C/EBPalpha.

Various mechanical stimuli affect differentiation of mesoderm-derived cells such as osteoblasts or myoblasts, suggesting that adipogenesis may also be influenced by mechanical stimulation. However, effects of mechanical stimuli on adipogenesis are scarcely known. Compressive force was applied to a human preadipocyte cell line, SGBS. Levels of gene expression were estimated by real-time reverse transcription-polymerase chain reaction. The accumulation of lipids was evaluated by Sudan III or Oil Red O staining. In SGBS cells subjected to a compressive force of 226 Pa for 12 h before adipogenic induction, adipogenesis was inhibited. Compressive force immediately after adipogenic induction did not affect the adipogenesis. The expression of peroxisome proliferator-activated receptor (PPAR) gamma2 and CCAAT/enhancer binding protein (C/EBP) alpha mRNA during adipogenesis was inhibited by compressive force, whereas C/EBPbeta and C/EBPdelta mRNA levels were unaffected. In preadipocytes, compressive force increased mRNA levels of Krüppel-like factor 2, preadipocyte factor 1, WNT10b, and cyclooxygenase-2 (COX-2) which are known as negative regulators for the PPARgamma2 and C/EBPalpha genes. Furthermore, a COX-2 inhibitor completely reversed the inhibition of adipogenesis by compressive force. In conclusion, compressive force inhibited adipogenesis by suppressing expression of PPARgamma2 and C/EBPalpha in a COX-2-dependent manner.