Activation of S6 signaling is associated with cell survival and multinucleation in hyperplastic skin after epidermal loss of AURORA-A Kinase

Weston Kenneth Ryan, Josiah Fernandez, Mikayla Katherine Peterson, David William Sheneman, Brendan Keefe Podell, Subhajyoti De, Enrique Carlo Torchia

Research output: Contribution to journalArticle

Abstract

The role of mitosis in the progression of precancerous skin remains poorly understood. To address this question, we deleted the mitotic Kinase Aurora-A (Aur-A) in hyperplastic mutant p53 mouse skin as an experimental tool to study the G2/M transition in precancerous keratinocytes and AUR-A’s role in this process. Epidermal Aur-A deletion (Aur-A epiΔ ) led to marked keratinocyte enlargement, pleomorphism, multinucleation, and attenuated induction of cell death. This phenotype was characteristic of slippage after a stalled mitosis. We also observed altered or impaired epidermal differentiation, indicative of a partial skin barrier defect. The upregulation of mTOR/PI3K signaling was implicated as a mechanism by which keratinocytes may evade cell death after AUR-A deficiency. This was evidenced by the ectopic expression of the pathway readout, p-S6, in the basal layer of Aur-A epiΔ skin and its mitotic upregulation in isolated keratinocytes. We further tested whether our findings were extended to skin carcinoma cells. The chemical inhibition of AUR-A led to a similar mitotic delay, polyploidy/multinucleation, and attenuated cell death in skin cancer cell lines. Moreover, inhibition of mTOR/PI3K signaling ameliorated the effects caused by the deficiency of AUR-A activity but was also associated with the persistence of mitotic p-S6 detection in surviving cancer cells. These results show the induction of multinucleation/polyploidy may be a compensatory state in keratinocytes that allows for cellular survival and maintenance of partial barrier function in face of aberrant cell division or differentiation. Moreover, mTOR/PI3K signaling is active in the mitosis of hyperplastic keratinocytes expressing mutant p53 and is further enhanced by stalled mitosis, indicating a potential resistance mechanism to the use of anti-mitotic drugs in the treatment of skin cancers.

Original languageEnglish (US)
Pages (from-to)548-564
Number of pages17
JournalCell Death and Differentiation
Volume26
Issue number3
DOIs
StatePublished - Mar 1 2019

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S 6
Keratinocytes
Cell Survival
Phosphotransferases
Mitosis
Skin
Phosphatidylinositol 3-Kinases
Polyploidy
Cell Death
Skin Neoplasms
Up-Regulation
Aurora Kinase A
Cell Division
Cell Differentiation
Maintenance
Carcinoma
Phenotype
Cell Line
Pharmaceutical Preparations
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Ryan, Weston Kenneth ; Fernandez, Josiah ; Peterson, Mikayla Katherine ; Sheneman, David William ; Podell, Brendan Keefe ; De, Subhajyoti ; Torchia, Enrique Carlo. / Activation of S6 signaling is associated with cell survival and multinucleation in hyperplastic skin after epidermal loss of AURORA-A Kinase. In: Cell Death and Differentiation. 2019 ; Vol. 26, No. 3. pp. 548-564.
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abstract = "The role of mitosis in the progression of precancerous skin remains poorly understood. To address this question, we deleted the mitotic Kinase Aurora-A (Aur-A) in hyperplastic mutant p53 mouse skin as an experimental tool to study the G2/M transition in precancerous keratinocytes and AUR-A’s role in this process. Epidermal Aur-A deletion (Aur-A epiΔ ) led to marked keratinocyte enlargement, pleomorphism, multinucleation, and attenuated induction of cell death. This phenotype was characteristic of slippage after a stalled mitosis. We also observed altered or impaired epidermal differentiation, indicative of a partial skin barrier defect. The upregulation of mTOR/PI3K signaling was implicated as a mechanism by which keratinocytes may evade cell death after AUR-A deficiency. This was evidenced by the ectopic expression of the pathway readout, p-S6, in the basal layer of Aur-A epiΔ skin and its mitotic upregulation in isolated keratinocytes. We further tested whether our findings were extended to skin carcinoma cells. The chemical inhibition of AUR-A led to a similar mitotic delay, polyploidy/multinucleation, and attenuated cell death in skin cancer cell lines. Moreover, inhibition of mTOR/PI3K signaling ameliorated the effects caused by the deficiency of AUR-A activity but was also associated with the persistence of mitotic p-S6 detection in surviving cancer cells. These results show the induction of multinucleation/polyploidy may be a compensatory state in keratinocytes that allows for cellular survival and maintenance of partial barrier function in face of aberrant cell division or differentiation. Moreover, mTOR/PI3K signaling is active in the mitosis of hyperplastic keratinocytes expressing mutant p53 and is further enhanced by stalled mitosis, indicating a potential resistance mechanism to the use of anti-mitotic drugs in the treatment of skin cancers.",
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Activation of S6 signaling is associated with cell survival and multinucleation in hyperplastic skin after epidermal loss of AURORA-A Kinase. / Ryan, Weston Kenneth; Fernandez, Josiah; Peterson, Mikayla Katherine; Sheneman, David William; Podell, Brendan Keefe; De, Subhajyoti; Torchia, Enrique Carlo.

In: Cell Death and Differentiation, Vol. 26, No. 3, 01.03.2019, p. 548-564.

Research output: Contribution to journalArticle

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AU - Ryan, Weston Kenneth

AU - Fernandez, Josiah

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AU - Sheneman, David William

AU - Podell, Brendan Keefe

AU - De, Subhajyoti

AU - Torchia, Enrique Carlo

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AB - The role of mitosis in the progression of precancerous skin remains poorly understood. To address this question, we deleted the mitotic Kinase Aurora-A (Aur-A) in hyperplastic mutant p53 mouse skin as an experimental tool to study the G2/M transition in precancerous keratinocytes and AUR-A’s role in this process. Epidermal Aur-A deletion (Aur-A epiΔ ) led to marked keratinocyte enlargement, pleomorphism, multinucleation, and attenuated induction of cell death. This phenotype was characteristic of slippage after a stalled mitosis. We also observed altered or impaired epidermal differentiation, indicative of a partial skin barrier defect. The upregulation of mTOR/PI3K signaling was implicated as a mechanism by which keratinocytes may evade cell death after AUR-A deficiency. This was evidenced by the ectopic expression of the pathway readout, p-S6, in the basal layer of Aur-A epiΔ skin and its mitotic upregulation in isolated keratinocytes. We further tested whether our findings were extended to skin carcinoma cells. The chemical inhibition of AUR-A led to a similar mitotic delay, polyploidy/multinucleation, and attenuated cell death in skin cancer cell lines. Moreover, inhibition of mTOR/PI3K signaling ameliorated the effects caused by the deficiency of AUR-A activity but was also associated with the persistence of mitotic p-S6 detection in surviving cancer cells. These results show the induction of multinucleation/polyploidy may be a compensatory state in keratinocytes that allows for cellular survival and maintenance of partial barrier function in face of aberrant cell division or differentiation. Moreover, mTOR/PI3K signaling is active in the mitosis of hyperplastic keratinocytes expressing mutant p53 and is further enhanced by stalled mitosis, indicating a potential resistance mechanism to the use of anti-mitotic drugs in the treatment of skin cancers.

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