Role of nuclear IL-2Ra in regulation of vascular smooth muscle cell senescence - Project Summary
Vascular aging impacts all perfused tissues and organs. Senescent vascular smooth muscle cells (VSMC)
accumulate in aging vessels, where the release of senescence-associated cytokines promotes chronic
inflammation, atherosclerosis, and the generation of more senescent cells. Given their significant
contributions to vascular pathology, senescent VSMC are now being viewed as a therapeutic target.
However, treatments to eliminate, reverse, or prevent VSMC senescence cannot be developed without
knowing the factors that drive senescence. New data from our laboratory suggests that one key factor in
this process is nuclear interleukin 2 receptor a. Our preliminary data show that IL-2Ra localizes to the
nucleus of quiescent VSMC but leaves the nucleus when VSMC are stimulated to proliferate. Senescent
VSMC, which do not divide when stimulated, continue to express IL-2Ra in the nucleus when cultured
under proliferative conditions. Nuclear localization of IL-2Ra may occur through the cytoplasmic tail, which
contains a cluster of basic amino acids consistent with DNA binding and nuclear localization. This C
terminal tail also contains two known phosphorylation sites. Treatment of VSMC with two different
phosphatase inhibitors significantly increased nuclear localization of IL-2Ra. Based on these findings, we
hypothesize that localization of IL-2Ra to the nucleus inhibits proliferation, and that irreversible localization
of IL-2Ra to the nucleus promotes senescence. This hypothesis will be addressed by the following aims:
Aim I: Define how IL-2Ra impacts VSMC proliferation and senescence. Aim II: Determine how the C
terminus, and its phosphorylation, impacts intracellular localization of IL-2Ra and VSMC senescence. Aim
III: Determine how IL-2Ra is retained in the nucleus of senescent VSMC. Results from this project will
establish that nuclear IL-2Ra directly impacts senescence in VSMC. These findings will provide a strong
rationale for future studies determining the mechanism by which nuclear IL-2Ra impacts cell division and
senescence, how transport of IL-2Ra is regulated, and how the absence of IL-2Ra affects VSMC biology
and pathology in vivo. In total, these future studies will define a new pathway for regulating cell division and
senescence in VSMC and potentially other cells expressing IL-2Ra.
