SMAD4 mutations and cross-talk between TGF-β/IFNγ signaling accelerate rates of DNA damage and cellular senescence, resulting in a segmental progeroid syndrome—the Myhre syndrome

Renuka Kandhaya-Pillai, Deyin Hou, Jiaming Zhang, Xiaomeng Yang, Goli Compoginis, Takayasu Mori, Tamara Tchkonia, George M. Martin, Fuki M. Hisama, James L. Kirkland, Junko Oshima

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

SMAD4 encodes a member of the SMAD family of proteins involved in the TGF-β signaling pathway. Potentially heritable, autosomal dominant, gain-of-function heterozygous variants of SMAD4 cause a rare developmental disorder, the Myhre syndrome, which is associated with a wide range of developmental and post-developmental phenotypes that we now characterize as a novel segmental progeroid syndrome. Whole-exome sequencing of a patient referred to our International Registry of Werner Syndrome revealed a heterozygous p.Arg496Cys variant of the SMAD4 gene. To investigate the role of SMAD4 mutations in accelerated senescence, we generated cellular models overexpressing either wild-type SMAD4 or mutant SMAD4-R496C in normal skin fibroblasts. We found that cells expressing the SMAD4-R496C mutant exhibited decreased proliferation and elevated expression of cellular senescence and inflammatory markers, including IL-6, IFNγ, and a TGF-β target gene, PAI-1. Here we show that transient exposure to TGF-β, an inflammatory cytokine, followed by chronic IFNγ stimulation, accelerated rates of senescence that were associated with increased DNA damage foci and SMAD4 expression. TGF-β, IFNγ, or combinations of both were not sufficient to reduce proliferation rates of fibroblasts. In contrast, TGF-β alone was able to induce preadipocyte senescence via induction of the mTOR protein. The mTOR inhibitor rapamycin mitigated TGF-β-induced expression of p21, p16, and DNA damage foci and improved replicative potential of preadipocytes, supporting the cell-specific response to this cytokine. These findings collectively suggest that persistent DNA damage and cross-talk between TGF-β/IFNγ pathways contribute to a series of molecular events leading to cellular senescence and a segmental progeroid syndrome.

Original languageEnglish (US)
JournalGeroScience
DOIs
StateAccepted/In press - 2021

Keywords

  • Cellular senescence
  • DNA damage
  • Gain of function SMAD4 mutations
  • IFNγ
  • Myhre syndrome
  • Segmental progeroid syndromes
  • TGF-β

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

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