Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Aging with ING: a comparative study of different forms of stress induced premature senescence

Uma Karthika Rajarajacholan and Karl Riabowol _

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Oncotarget. 2015; 6:34118-34127. https://doi.org/10.18632/oncotarget.5947

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Abstract

Uma Karthika Rajarajacholan1 and Karl Riabowol1,2

1 Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta Canada

2 Department of Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta Canada

Correspondence to:

Karl Riabowol, email:

Keywords: senescence, ING1a, epigenetic, Retinoblastoma, p16, Gerotarget

Received: August 03, 2015 Accepted: September 09, 2015 Published: October 01, 2015

Abstract

Cell senescence contributes to organismal aging and is induced by telomere erosion and an ensuing DNA damage signal as cells reach the end of their replicative lifespan in vitro or in vivo. Stresses induced by oncogene or tumor suppressor hyperactivation, oxidative stress, ionizing radiation and other DNA damaging agents result in forms of stress induced premature senescence (SIPS) that show similarities to replicative senescence. Since replicative senescence and SIPS occur over many days and many population doublings of the mass cultures of primary cells used to study senescence, the sequence of events that occur downstream of senescence signaling can be challenging to define. Here we compare a new model of ING1a-induced senescence with several other forms of senescence. The ING1a epigenetic regulator synchronously induces senescence in mass cultures several-fold faster than all other agents, taking 24 and 36 hours to activate the Rb/ p16INK4a, but not the p53 tumor suppressor axis to efficiently induce senescence. ING1a induces expression of intersectin 2, a scaffold protein necessary for endocytosis, altering the stoichiometry of endocytosis proteins, subsequently blocking growth factor uptake leading to activation of Rb signaling to block cell growth. ING1a acts as a novel link in the activation of the Rb pathway that can impose senescence in the absence of activating p53-mediated DNA damage signaling, and should prove useful in defining the molecular events contributing to Rb-induced senescence.


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