Up-Regulation of p27Kip1 by Progestins Is Involved in the Growth Suppression of the Normal and Malignant Human Endometrial Glandular Cells

Progestins are known to suppress the growth of normal human endometrial glands and endometrial carcinomas possessing PRs. To elucidate the molecular mechanisms of progestin-induced growth inhibition, the expression and functional involvement of p27Kip1 (p27), a cyclin-dependent-kinase inhibitor, was...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2001-10, Vol.142 (10), p.4182-4188
Main Authors: Shiozawa, Tanri, Horiuchi, Akiko, Kato, Kiyoshi, Obinata, Miyuki, Konishi, Ikuo, Fujii, Shingo, Nikaido, Toshio
Format: Article
Language:English
Subjects:
Acetic acid
Biodegradation
Carcinoma
Complex formation
Cyclin-dependent kinase inhibitor p27
Degradation
Endometrium
Epithelial cells
Epithelium
Gene expression
Immunoprecipitation
Kinases
Medroxyprogesterone acetate
Molecular modelling
Progesterone
Progestin
Proteins
Tumor cell lines
Up-regulation
Uterine cancer
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Summary:Progestins are known to suppress the growth of normal human endometrial glands and endometrial carcinomas possessing PRs. To elucidate the molecular mechanisms of progestin-induced growth inhibition, the expression and functional involvement of p27Kip1 (p27), a cyclin-dependent-kinase inhibitor, was investigated using cultured normal endometrial glandular cells and endometrial carcinoma cell lines (Ishikawa; PR-positive, KLE; PR-negative). Growth of the normal endometrial glandular cells and Ishikawa cells was suppressed by treatment with progesterone and medroxyprogesterone acetate, respectively, in association with an increase in p27 protein expression. Immunoprecipitation revealed that progestins accelerated the complex formation of p27 and cdk2 in both types of cells. However, treatment with progestins did not show any marked alterations in the mRNA expression of p27 in either normal glandular cells or Ishikawa cells. On the other hand, p27 protein degradation experiments indicated that treatment with progesterone and medroxyprogesterone acetate prolonged the degradation time of the normal endometrial glandular cells and Ishikawa cells, respectively. Forced expression of the p27 protein using a p27 expression plasmid reduced the growth activity of normal endometrial glandular cells. These findings suggest that p27 is functionally involved in progestin-induced growth suppression of normal and malignant endometrial epithelial cells and that up-regulation of the p27 protein by progestins possibly occurs via posttranslational mechanisms.
ISSN:0013-7227
1945-7170
DOI:10.1210/endo.142.10.8455