Pituitary senescence: the evolving role of Pttg - PubMed (original) (raw)

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Pituitary senescence: the evolving role of Pttg

Vera Chesnokova et al. Mol Cell Endocrinol. 2010.

Abstract

Despite the high prevalence of pituitary adenomas they are invariably benign, indicative of unique intrinsic mechanisms controlling pituitary cell proliferation. Cellular senescence is characterized by a largely irreversible cell cycle arrest and constitutes a strong anti-proliferative response, which can be triggered by DNA damage, chromosomal instability and aneuploidy, loss of tumor suppressive signaling or oncogene activation. In vivo senescence is an important protective mechanism against cancer. Here we discuss prospective mechanisms underlying senescence-associated molecular pathways activated in benign pituitary adenomas. Both deletion and over-expression of pituitary tumor transforming gene (Pttg) promote chromosomal instability and aneuploidy. Pttg deletion abrogates tumor development by activating p53/p21-dependent senescence pathways. Abundant PTTG in GH-secreting pituitary adenomas also triggers p21-dependent senescence. Pituitary p21 may therefore safeguard against further chromosomal instability by constraining pituitary tumor growth. These observations point to senescence as a target for effective therapy for both tumor silencing and growth restraint towards development of pituitary malignancy.

2010 Elsevier Ireland Ltd. All rights reserved.

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Figures

Fig. 1

Fig. 1

Senescence pathways (Adapted from: Chesnokova et al. Pituitary Today II, Front Horm Res. Basel, Karger 2010, v.38, pp.7-14)

Fig.2

Fig.2

Pttg deletion in murine pituitary gland and Pttg overexpression in human GH-cell adenoma result in activation of p53/p21 senescence pathway and senescence. A) Induced p53 and p21, and B) increased SA-β-gal activity (blue) in _Pttg_-deficient pituitary glands (Chesnokova, Cancer Res 2007); C) Confocal image of double fluorescence immunohistochemistry of p21 (green) and β-galactosidase (red) proteins co-expression in human pituitary adenomatous but not in normal adjacent tissue. Right panel-high resolution (× 63) image of the same slide (Chesnokova PNAS 2008).

Fig.3

Fig.3

Proposed model for p21-induced senescence in the hypoplastic _Pttg_-null pituitary gland and _Pttg_-overexpressing pituitary adenomas (Chesnokova, PNAS 2008).

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