Transforming growth factor-β, estrogen, and progesterone converge on the regulation of p27Kip1 in the normal and malignant endometrium

Jon Lecanda, Trilok V. Parekh, Patricia Gama, Ke Lin, Vladimir Liarski, Seth Uretsky, Khush Mittal, Leslie I. Gold

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Hormones and growth factors regulate endometrial cell growth. Disrupted transforming growth factor-β (TGF-β) signaling in primary endometrial carcinoma (ECA) cells leads to loss of TGF-β-mediated growth inhibition, which we show herein results in lack of up-regulation of the cyclin-dependent kinase inhibitor p27Kip1 (p27) to arrest cells in G1 phase of the cell cycle. Conversely, in normal primary endometrial epithelial cells (EECs), TGF-β induces a dose-dependent increase in p27 protein, with a total 3.6-fold maximal increase at 100 pmol/L TGF-β, which was 2-fold higher in the nuclear fraction; mRNA levels were unaffected. In addition, ECA tissue lysates show a high rate of ubiquitin-mediated degradation of p27 compared with normal secretory-phase endometrial tissue (SE) such that 4% and 89% of recombinant p27 added to the lysates remains after 3 and 20 h, respectively. These results are reflected in vivo as ECA tissue lacks p27 compared with high expression of p27 in SE (P ≤ 0.001). Furthermore, we show that estrogen treatment of EECs causes mitogen-activated protein kinase-driven proteasomal degradation of p27 whereas progesterone induces a marked increase in p27 in both normal EECs and ECA cells. Therefore, these data suggest that TGF-β induces accumulation of p27 for normal growth regulation of EECs. However, in ECA, in addition to enhanced proteasomal degradation of p27, TGF-β cannot induce p27 levels due to dysregulated TGF-β signaling, thereby causing 17β-estradiol-driven p27 degradation to proceed unchecked for cell cycle progression. Thus, p27 may be a central target for growth regulation of normal endometrium and in the pathogenesis of ECA.

Original languageEnglish (US)
Pages (from-to)1007-1018
Number of pages12
JournalCancer Research
Volume67
Issue number3
DOIs
StatePublished - Feb 1 2007
Externally publishedYes

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Transforming Growth Factors
Endometrium
Endometrial Neoplasms
Progesterone
Estrogens
Epithelial Cells
Growth
Cell Cycle
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases
G1 Phase
Ubiquitin
Mitogen-Activated Protein Kinases
Estradiol
Intercellular Signaling Peptides and Proteins
Up-Regulation
Hormones
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Lecanda, Jon ; Parekh, Trilok V. ; Gama, Patricia ; Lin, Ke ; Liarski, Vladimir ; Uretsky, Seth ; Mittal, Khush ; Gold, Leslie I. / Transforming growth factor-β, estrogen, and progesterone converge on the regulation of p27Kip1 in the normal and malignant endometrium. In: Cancer Research. 2007 ; Vol. 67, No. 3. pp. 1007-1018.
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Transforming growth factor-β, estrogen, and progesterone converge on the regulation of p27Kip1 in the normal and malignant endometrium. / Lecanda, Jon; Parekh, Trilok V.; Gama, Patricia; Lin, Ke; Liarski, Vladimir; Uretsky, Seth; Mittal, Khush; Gold, Leslie I.

In: Cancer Research, Vol. 67, No. 3, 01.02.2007, p. 1007-1018.

Research output: Contribution to journalArticle

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T1 - Transforming growth factor-β, estrogen, and progesterone converge on the regulation of p27Kip1 in the normal and malignant endometrium

AU - Lecanda, Jon

AU - Parekh, Trilok V.

AU - Gama, Patricia

AU - Lin, Ke

AU - Liarski, Vladimir

AU - Uretsky, Seth

AU - Mittal, Khush

AU - Gold, Leslie I.

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AB - Hormones and growth factors regulate endometrial cell growth. Disrupted transforming growth factor-β (TGF-β) signaling in primary endometrial carcinoma (ECA) cells leads to loss of TGF-β-mediated growth inhibition, which we show herein results in lack of up-regulation of the cyclin-dependent kinase inhibitor p27Kip1 (p27) to arrest cells in G1 phase of the cell cycle. Conversely, in normal primary endometrial epithelial cells (EECs), TGF-β induces a dose-dependent increase in p27 protein, with a total 3.6-fold maximal increase at 100 pmol/L TGF-β, which was 2-fold higher in the nuclear fraction; mRNA levels were unaffected. In addition, ECA tissue lysates show a high rate of ubiquitin-mediated degradation of p27 compared with normal secretory-phase endometrial tissue (SE) such that 4% and 89% of recombinant p27 added to the lysates remains after 3 and 20 h, respectively. These results are reflected in vivo as ECA tissue lacks p27 compared with high expression of p27 in SE (P ≤ 0.001). Furthermore, we show that estrogen treatment of EECs causes mitogen-activated protein kinase-driven proteasomal degradation of p27 whereas progesterone induces a marked increase in p27 in both normal EECs and ECA cells. Therefore, these data suggest that TGF-β induces accumulation of p27 for normal growth regulation of EECs. However, in ECA, in addition to enhanced proteasomal degradation of p27, TGF-β cannot induce p27 levels due to dysregulated TGF-β signaling, thereby causing 17β-estradiol-driven p27 degradation to proceed unchecked for cell cycle progression. Thus, p27 may be a central target for growth regulation of normal endometrium and in the pathogenesis of ECA.

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