Hypophosphorylated pRb knock-in mice exhibit hallmarks of aging and vitamin C-preventable diabetes

Zhe Jiang*, Huiqin Li, Stephanie A. Schroer, Veronique Voisin, Young Jun Ju, Marek Pacal, Natalie Erdmann, Wei Shi, Philip E.D. Chung, Tao Deng, Nien Jung Chen, Giovanni Ciavarra, Alessandro Datti, Tak W. Mak, Lea Harrington, Frederick A. Dick, Gary D. Bader, Rod Bremner, Minna Woo, Eldad Zacksenhaus

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Despite extensive analysis of pRB phosphorylation in vitro, how this modification influences development and homeostasis in vivo is unclear. Here, we show that homozygous Rb∆K4 and Rb∆K7 knock-in mice, in which either four or all seven phosphorylation sites in the C-terminal region of pRb, respectively, have been abolished by Ser/Thr-to-Ala substitutions, undergo normal embryogenesis and early development, notwithstanding suppressed phosphorylation of additional upstream sites. Whereas Rb∆K4 mice exhibit telomere attrition but no other abnormalities, Rb∆K7 mice are smaller and display additional hallmarks of premature aging including infertility, kyphosis, and diabetes, indicating an accumulative effect of blocking pRb phosphorylation. Diabetes in Rb∆K7 mice is insulin-sensitive and associated with failure of quiescent pancreatic β-cells to re-enter the cell cycle in response to mitogens, resulting in induction of DNA damage response (DDR), senescence-associated secretory phenotype (SASP), and reduced pancreatic islet mass and circulating insulin level. Pre-treatment with the epigenetic regulator vitamin C reduces DDR, increases cell cycle re-entry, improves islet morphology, and attenuates diabetes. These results have direct implications for cell cycle regulation, CDK-inhibitor therapeutics, diabetes, and longevity.

Original languageEnglish
Article numbere106825
JournalEMBO Journal
Volume41
Issue number4
DOIs
StatePublished - 15 Feb 2022

Keywords

  • aging
  • diabetes
  • knock-in mice
  • pRB
  • retinoblastoma
  • senescence
  • vitamin C

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