Small proline-rich protein 2B drives stress-dependent p53 degradation and fibroblast proliferation in heart failure

Proc Natl Acad Sci U S A. 2018 Apr 10;115(15):E3436-E3445. doi: 10.1073/pnas.1717423115. Epub 2018 Mar 26.


Heart disease is associated with the accumulation of resident cardiac fibroblasts (CFs) that secrete extracellular matrix (ECM), leading to the development of pathological fibrosis and heart failure. However, the mechanisms underlying resident CF proliferation remain poorly defined. Here, we report that small proline-rich protein 2b (Sprr2b) is among the most up-regulated genes in CFs during heart disease. We demonstrate that SPRR2B is a regulatory subunit of the USP7/MDM2-containing ubiquitination complex. SPRR2B stimulates the accumulation of MDM2 and the degradation of p53, thus facilitating the proliferation of pathological CFs. Furthermore, SPRR2B phosphorylation by nonreceptor tyrosine kinases in response to TGF-β1 signaling and free-radical production potentiates SPRR2B activity and cell cycle progression. Knockdown of the Sprr2b gene or inhibition of SPRR2B phosphorylation attenuates USP7/MDM2 binding and p53 degradation, leading to CF cell cycle arrest. Importantly, SPRR2B expression is elevated in cardiac tissue from human heart failure patients and correlates with the proliferative state of patient-derived CFs in a process that is reversed by insulin growth factor-1 signaling. These data establish SPRR2B as a unique component of the USP7/MDM2 ubiquitination complex that drives p53 degradation, CF accumulation, and the development of pathological cardiac fibrosis.

Keywords: SPRR2B; fibroblast; heart; p53; proliferation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Cell Proliferation*
  • Cornified Envelope Proline-Rich Proteins / genetics
  • Cornified Envelope Proline-Rich Proteins / metabolism*
  • Fibroblasts / metabolism*
  • Heart Failure / genetics
  • Heart Failure / metabolism*
  • Heart Failure / physiopathology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Myocardium / metabolism
  • Proteolysis
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • Cornified Envelope Proline-Rich Proteins
  • SPRR2B protein, human
  • Sprr2b protein, mouse
  • TP53 protein, human
  • Transforming Growth Factor beta1
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53