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p21(Cip1) restrains pituitary tumor growth

Vera Chesnokova1, Svetlana Zonis, Kalman Kovacs

  • 1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

Proceedings of the National Academy of Sciences of the United States of America
|November 5, 2008
PubMed

Insights

Pituitary tumor transforming gene (Pttg) deletion or overexpression promotes pituitary cell aneuploidy and p53/p21-dependent senescence. This p21-dependent senescence constrains pituitary tumor growth, explaining the rarity of pituitary carcinomas.

Area of Science:

  • Endocrinology
  • Oncology
  • Molecular Biology

Background:

  • Pituitary adenomas are typically benign, suggesting inherent protective proliferative mechanisms.
  • Pituitary tumor transforming gene (Pttg) plays a role in pituitary tumor development.
  • The cell cycle inhibitor p21 is implicated in tumor suppression and senescence.

Purpose of the Study:

  • To investigate the role of Pttg and p21 in pituitary tumor development and proliferation.
  • To elucidate the mechanisms by which pituitary cell proliferation is regulated.
  • To understand the low incidence of pituitary carcinomas.

Main Methods:

  • Utilized genetically modified mouse models (Rb(+/-)Pttg(-/-) and Rb(+/-)Pttg(-/-)p21(-/-)).
  • Analyzed pituitary tumor growth rates and cell proliferation.
  • Examined gene expression of p21 and ATM in pituitary tumor cells.
  • Assessed senescence markers (p21, SA-beta-galactosidase) in human pituitary tumors.

Main Results:

  • Pttg deletion induced p21 and abrogated tumor development in Rb(+/-)Pttg(-/-) mice.
  • p21 disruption restored proliferation and increased pituitary tumor incidence in triple mutant mice.
  • Pttg overexpression or deletion promoted aneuploidy and p53/p21-dependent senescence, particularly in GH-secreting cells.
  • High PTTG levels correlated with increased p21 and senescence in human GH-producing pituitary adenomas.

Conclusions:

  • Pttg influences pituitary cell aneuploidy and senescence through p53/p21.
  • p21 acts as a tumor suppressor in the pituitary by inducing senescence.
  • This p21-mediated senescence mechanism likely accounts for the low incidence of pituitary carcinomas.

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