The TGF-β1/p53/PAI-1 Signaling Axis in Vascular Senescence: Role of Caveolin-1

Biomolecules
Rohan SamarakoonP J Higgins

Abstract

Stress-induced premature cellular senescence is a significant factor in the onset of age-dependent disease in the cardiovascular system. Plasminogen activator inhibitor-1 (PAI-1), a major TGF-β1/p53 target gene and negative regulator of the plasmin-based pericellular proteolytic cascade, is elevated in arterial plaques, vessel fibrosis, arteriosclerosis, and thrombosis, correlating with increased tissue TGF-β1 levels. Additionally, PAI-1 is necessary and sufficient for the induction of p53-dependent replicative senescence. The mechanism of PAI-1 transcription in senescent cells appears to be dependent on caveolin-1 signaling. Src kinases are upstream effectors of both FAK and caveolin-1 activation as FAKY577,Y861 and caveolin-1Y14 phosphorylation are not detected in TGF-β1-stimulated src family kinase (pp60c-src, Yes, Fyn) triple-deficient (SYF-/-/-) cells. However, restoration of pp60c-src expression in SYF-null cells rescued both caveolin-1Y14 phosphorylation and PAI-1 induction in response to TGF-β1. Furthermore, TGF-β1-initiated Src phosphorylation of caveolin-1Y14 is critical in Rho-ROCK-mediated suppression of the SMAD phosphatase PPM1A maintaining and, accordingly, SMAD2/3-dependent transcription of the PAI-1 gene. Impor...Continue Reading

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Citations

Mar 19, 2020·Biomolecules·Mahmut MijitAntonio Giordano
Oct 1, 2020·International Journal of Molecular Sciences·Fasih Ahmad Rahman, Matthew Paul Krause
Dec 7, 2020·Clinica Chimica Acta; International Journal of Clinical Chemistry·Kai HouXuping Qin
Nov 5, 2020·International Journal of Molecular Sciences·Ru-Hsiu ChengJiiang-Huei Jeng
Aug 29, 2021·Biochemical and Biophysical Research Communications·Jiao DongHideharu Hibi

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Methods Mentioned

BETA
ubiquitination

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