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ATM and P53 differentially regulate pancreatic beta cell survival in Ins1E cells

Celina Uhlemeyer1,2, Nadine Müller1,2, Kerstin Grieß1,2

  • 1Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

Plos One
|August 19, 2020
PubMed

Insights

Ataxia Telangiectasia Mutated (ATM) and tumor protein P53 (P53) differentially regulate pancreatic beta cell survival under various diabetic stresses. ATM influences P53-dependent and independent pathways, highlighting distinct roles in beta cell protection.

Area of Science:

  • Cell Biology
  • Endocrinology
  • Molecular Biology

Background:

  • Pancreatic beta cell death is central to type 1 and type 2 diabetes (T1D/T2D).
  • The roles of DNA damage response (DDR) proteins, including Ataxia Telangiectasia Mutated (ATM) and tumor protein P53 (P53), in beta cell survival are not fully understood.
  • ATM is a kinase upstream of P53 and has been linked to T2D.

Purpose of the Study:

  • To investigate and compare the effects of ATM and P53 ablation on beta cell survival under diverse diabetogenic stresses.
  • To elucidate the differential regulation of beta cell apoptosis by ATM and P53 in response to DNA damage, inflammation, lipotoxicity, and endoplasmic reticulum (ER) stress.

Main Methods:

  • Utilized the rat beta cell line Ins1E for in vitro experiments.
  • Assessed beta cell apoptosis following exposure to streptozotocin (STZ), inflammatory stimuli, lipotoxicity, and tunicamycin (ER stress inducer).
  • Examined the impact of ATM and P53 knockdown or inhibition on cell survival.

Main Results:

  • Both ATM and P53 regulate streptozotocin (STZ)-induced DNA damage apoptosis, with ATM acting as a key activator of P53.
  • ATM and P53 both control lipotoxic beta cell apoptosis.
  • ATM, but not P53, influences inflammatory beta cell death.
  • ATM inhibition or knockdown exacerbates tunicamycin-induced ER stress apoptosis, whereas P53 knockdown does not.

Conclusions:

  • ATM and P53 play differential roles in regulating beta cell survival against various diabetogenic insults.
  • ATM can mediate beta cell survival through P53-independent pathways, depending on the specific cellular stress.
  • These findings offer insights into the molecular mechanisms underlying beta cell dysfunction in diabetes.

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