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Oncogene-induced DNA damage: cyclic AMP steps into the ring
James A. Fagin, John H. Petrini
James A. Fagin, John H. Petrini
Published September 28, 2020
Citation Information: J Clin Invest. 2020;130(11):5668-5670. https://doi.org/10.1172/JCI142237.
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Oncogene-induced DNA damage: cyclic AMP steps into the ring

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Abstract

Growth hormone–secreting (GH-secreting) pituitary tumors are driven by oncogenes that induce cAMP signaling. In this issue of the JCI, Ben-Shlomo et al. performed a whole-exome study of pituitary adenomas. GH-secreting tumors had a high frequency of whole chromosome or chromosome arm copy number alterations and were associated with an increase in the tumor protein p53 and the cyclin-dependent kinase inhibitor p21WAF1/CIP1, which are findings consistent with induction of a response to DNA damage. Further, treatment of mouse pituitary cells with cAMP pathway agonists in vitro and in vivo elicited biomarkers of DNA replication stress or double-strand breaks. The findings of Ben Shlomo et al. indicate that oncoproteins that drive constitutively high cAMP signaling pathway output in susceptible cell types can elicit DNA replication stress and may promote genomic instability.

Authors

James A. Fagin, John H. Petrini

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Figure 1

Potential mechanisms for induction of the DNA damage response pathway in GH-secreting pituitary adenomas.

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Potential mechanisms for induction of the DNA damage response pathway in...
Somatotroph tumors harbor widespread chromosomal copy number abnormalities. The major disease drivers include germline or somatic mutations of signaling effectors in the cAMP signaling pathway or, less commonly, ectopic secretion of GHRH by neuroendocrine (NE) tumors. The mutant proteins activate cAMP signaling, which may be further augmented through impaired negative feedback by downregulation of the phosphodiesterase PDE4D. Ben-Shlomo et al. (9) showed that human GH–secreting tumors had an increase in p53 and the cyclin-dependent kinase inhibitor p21CIP1/WAF1, consistent with a response to DNA damage. These results were supported by in vitro and in vivo experiments that showed that potent activation of cAMP signaling increased γH2AX and Olive tail moment in comet assays in mouse pituitary cells. The mechanisms that induce the DNA damage response are unknown but could involve DNA replication stress and/or collisions between transcriptional and DNA replication complexes, such as stalled DNA replication forks or unresolved R loops. DNA damage occurs in response to illegitimate activation of a variety of oncoproteins. The finding that cAMP signaling is implicated in the induction of the DNA damage response may be relevant to other endocrine cell lineages in which the cAMP pathway regulates cell proliferation and hormone gene expression.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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