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p53 suppresses carcinoma progression by inhibiting mTOR pathway activation

Oncogene volume 34, pages 589–599 (2015)Cite this article

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Abstract

Genetic alterations in human cancers and murine models indicate that retinoblastoma (Rb) and p53 have critical tumor suppressive functions in retinoblastoma, a tumor of neural origin, and neuroendocrine tumors including small cell lung cancer and medullary thyroid cancer (MTC). Rb inactivation is the initiating lesion in retinoblastoma and current models propose that induction of apoptosis is a key p53 tumor suppressive function. Genetic studies in mice, however, indicate that other undefined p53 tumor suppressive functions are operative in vivo. How p53 loss cooperates with Rb inactivation to promote carcinogenesis is also not fully understood. In the current study, genetically engineered mice were generated to determine the role of Rb and p53 in MTC pathogenesis and test the hypothesis that p53 suppresses carcinogenesis by inhibiting mammalian target of rapamycin (mTOR) signaling. Conditional Rb ablation resulted in thyroid tumors mimicking human MTC, and additional p53 loss led to rapid tumor progression. p53 suppressed tumorigenesis by inhibiting cell cycle progression, but did not induce apoptosis. On the contrary, p53 loss led to increased apoptosis that had to be overcome for tumor progression. The mTOR activity was markedly increased in p53-deficient tumors and rapamycin treatment suppressed tumor cell growth, identifying mTOR inhibition as a critical p53 tumor suppressive function. Rapamycin treatment did not result in AKT/mitogen-activated protein kinase activation, providing evidence that this feedback mechanism operative in other cancers is not a general response to mTORC1 inhibition. Together, these studies provide mechanistic links between genetic alterations and aberrant signaling pathways critical in carcinogenesis, and identify essential Rb and p53 tumor suppressive functions in vivo.

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Acknowledgements

We thank Mingyan Yang and Susan E Wert for technical expertise, Veterinary Services for excellent animal care, and Susanne I Wells and Elizabeth E Hoskins for reagents and technical expertise. This work was supported by grants from the American Cancer Society RSG-10-194-01-TBG and NIH/NHLBI RO1 HL079193 (to KAW-B).

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  1. Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    N Akeno, A L Miller, X Ma & K A Wikenheiser-Brokamp

  2. Pulmonary Biology, Cincinnati Children’s Hospital Medical Center and Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    K A Wikenheiser-Brokamp

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Correspondence to K A Wikenheiser-Brokamp.

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Akeno, N., Miller, A., Ma, X. et al. p53 suppresses carcinoma progression by inhibiting mTOR pathway activation. Oncogene 34, 589–599 (2015). https://doi.org/10.1038/onc.2013.589

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