<scp>PTEN</scp> controls β‐cell regeneration in aged mice by regulating cell cycle inhibitor p16 ^<i>ink4a</i>

<jats:title>Summary</jats:title> <jats:p> Tissue regeneration diminishes with age, concurrent with declining hormone levels including growth factors such as insulin‐like growth factor‐1 ( <jats:styled-content style="fixed-case">IGF</jats:styled-content> ‐1). We investigated the molecular basis for such decline in pancreatic β‐cells where loss of proliferation occurs early in age and is proposed to contribute to the pathogenesis of diabetes. We studied the regeneration capacity of β‐cells in mouse model where <jats:styled-content style="fixed-case">PI</jats:styled-content> 3 <jats:styled-content style="fixed-case">K</jats:styled-content> / <jats:styled-content style="fixed-case">AKT</jats:styled-content> pathway downstream of insulin/ <jats:styled-content style="fixed-case">IGF</jats:styled-content> ‐1 signaling is upregulated by genetic deletion of <jats:italic>Pten</jats:italic> ( <jats:italic>phosphatase and tensin homologue deleted on chromosome 10</jats:italic> ) specifically in insulin‐producing cells. In this model, <jats:styled-content style="fixed-case">PTEN</jats:styled-content> loss prevents the decline in proliferation capacity in aged β‐cells and restores the ability of aged β‐cells to respond to injury‐induced regeneration. Using several animal and cell models where we can manipulate <jats:styled-content style="fixed-case">PTEN</jats:styled-content> expression, we found that <jats:styled-content style="fixed-case">PTEN</jats:styled-content> blocks cell cycle re‐entry through a novel pathway leading to an increase in p16 <jats:sup> <jats:italic>ink4a</jats:italic> </jats:sup> , a cell cycle inhibitor characterized for its role in cellular senescence/aging. A downregulation in p16 <jats:sup> <jats:italic>ink4a</jats:italic> </jats:sup> occurs when <jats:styled-content style="fixed-case">PTEN</jats:styled-content> is lost as a result of cyclin <jats:styled-content style="fixed-case">D</jats:styled-content> 1 induction and the activation of <jats:styled-content style="fixed-case">E</jats:styled-content> 2 <jats:styled-content style="fixed-case">F</jats:styled-content> transcription factors. The activation of <jats:styled-content style="fixed-case">E</jats:styled-content> 2 <jats:styled-content style="fixed-case">F</jats:styled-content> transcriptional factors leads to methylation of p16 <jats:sup> <jats:italic>ink4a</jats:italic> </jats:sup> promoter, an event that is mediated by the upregulation of polycomb protein, <jats:styled-content style="fixed-case">E</jats:styled-content> zh2. These analyses establish a novel <jats:styled-content style="fixed-case">PTEN</jats:styled-content> /cyclin <jats:styled-content style="fixed-case">D</jats:styled-content> 1/ <jats:styled-content style="fixed-case">E</jats:styled-content> 2 <jats:styled-content style="fixed-case">F</jats:styled-content> / <jats:styled-content style="fixed-case">E</jats:styled-content> zh2/p16 <jats:sup> <jats:italic>ink4a</jats:italic> </jats:sup> signaling network responsible for the aging process and provide specific evidence for a molecular paradigm that explain how decline in growth factor signals such as <jats:styled-content style="fixed-case">IGF</jats:styled-content> ‐1 (through <jats:styled-content style="fixed-case">PTEN</jats:styled-content> / <jats:styled-content style="fixed-case">PI</jats:styled-content> 3 <jats:styled-content style="fixed-case">K</jats:styled-content> signaling) may control regeneration and the lack thereof in aging cells. </jats:p>