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Updated: May 8, 2026
Techniques to Induce and Quantify Cellular Senescence
Published on: May 1, 2017
Growth hormone is a cellular senescence target in pituitary and nonpituitary cells
Vera Chesnokova1, Cuiqi Zhou, Anat Ben-Shlomo
1Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Abstract:
Premature proliferative arrest in benign or early-stage tumors induced by oncoproteins, chromosomal instability, or DNA damage is associated with p53/p21 activation, culminating in either senescence or apoptosis, depending on cell context. Growth hormone (GH) elicits direct peripheral metabolic actions as well as growth effects mediated by insulin-like growth factor 1 (IGF1). Locally produced peripheral tissue GH, in contrast to circulating pituitary-derived endocrine GH, has been proposed to be both proapoptotic and prooncogenic. Pituitary adenomas expressing and secreting GH are invariably benign and exhibit DNA damage and a senescent phenotype. We therefore tested effects of nutlin-induced p53-mediated senescence in rat and human pituitary cells. We show that DNA damage senescence induced by nutlin triggers the p53/p21 senescent pathway, with subsequent marked induction of intracellular pituitary GH in vitro. In contrast, GH is not induced in cells devoid of p53. Furthermore we show that p53 binds specific GH promoter motifs and enhances GH transcription and secretion in senescent pituitary adenoma cells and also in nonpituitary (human breast and colon) cells. In vivo, treatment with nutlin results in up-regulation of both p53 and GH in the pituitary gland, as well as increased GH expression in nonpituitary tissues (lung and liver). Intracrine GH acts in pituitary cells as an apoptosis switch for p53-mediated senescence, likely protecting the pituitary adenoma from progression to malignancy. Unlike in the pituitary, in nonpituitary cells GH exerts antiapoptotic properties. Thus, the results show that GH is a direct p53 transcriptional target and fulfills criteria as a p53 target gene. Induced GH is a readily measurable cell marker for p53-mediated cellular senescence.
Insights
Growth hormone (GH) is a direct target of the tumor suppressor p53, acting as a marker for cellular senescence. Induced GH in pituitary cells switches from pro- to anti-apoptotic, preventing tumor progression.
Area of Science:
- Molecular Biology
- Cell Biology
- Endocrinology
Background:
- Cellular senescence, triggered by DNA damage or oncoproteins, involves p53/p21 activation and leads to either senescence or apoptosis.
- Growth hormone (GH) has diverse roles, with locally produced GH proposed as both proapoptotic and pro-oncogenic.
- Pituitary adenomas secreting GH are benign, showing DNA damage and senescence, suggesting a link between p53, GH, and tumor suppression.
Purpose of the Study:
- To investigate the effects of nutlin-induced p53-mediated senescence on GH production in pituitary cells.
- To determine if GH is a direct transcriptional target of p53.
- To explore the role of GH in p53-mediated senescence and its impact on tumor progression.
Main Methods:
- Utilized rat and human pituitary cells, including those with and without p53.
- Administered nutlin to induce p53-mediated senescence and DNA damage.
- Analyzed GH transcription, secretion, and binding to GH promoter motifs via p53.
- Examined p53 and GH expression in vivo in pituitary and non-pituitary tissues.
Main Results:
- Nutlin-induced senescence markedly increased intracellular GH in p53-positive pituitary cells, but not in p53-deficient cells.
- p53 directly binds to GH promoter motifs, enhancing GH transcription and secretion in senescent pituitary adenoma cells and non-pituitary cells.
- In vivo, nutlin treatment upregulated p53 and GH in the pituitary and increased GH expression in lung and liver tissues.
- Intracrine GH acts as an apoptosis switch in senescent pituitary cells, promoting survival and preventing malignant progression.
Conclusions:
- Growth hormone (GH) is a direct transcriptional target of p53 and a marker for p53-mediated cellular senescence.
- In pituitary cells, induced GH acts as an apoptosis switch, protecting against tumor malignancy.
- In non-pituitary cells, GH exhibits anti-apoptotic properties, highlighting context-dependent functions.
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