PIM2 interacts with tristetraprolin and promotes breast cancer tumorigenesis

Mol Oncol. 2018 May;12(5):690-704. doi: 10.1002/1878-0261.12192. Epub 2018 Apr 14.

Abstract

Tristetraprolin (TTP) is an AU-rich element-binding protein that regulates mRNA stability and plays important roles in cancer. The mechanisms by which TTP is regulated in breast cancer are poorly understood. Using multiple biochemical approaches, we found that proviral insertion in murine lymphomas 2 (PIM2) is a novel binding partner of TTP. Interestingly, PIM2 decreased TTP protein levels independent of its kinase activity. PIM2 instead targeted TTP protein for degradation via the ubiquitin-proteasome pathway. Furthermore, immunohistochemical staining showed that PIM2 and TTP protein levels were negatively correlated in human breast cancer samples. Indeed, PIM2 overexpression de-repressed TTP-mediated inhibition of breast cancer cell proliferation and migration in vitro and promoted breast tumor xenograft growth in vivo. These findings demonstrate an important role for the PIM2-TTP complex in breast cancer tumorigenesis, suggesting that PIM2 may represent a potential therapeutic target for breast cancer treatment.

Keywords: cancer; cell proliferation; degradation; proviral insertion in murine lymphomas 2; tristetraprolin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology*
  • Cell Line
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice, Nude
  • Middle Aged
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Domains
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Tristetraprolin / chemistry
  • Tristetraprolin / genetics
  • Tristetraprolin / metabolism*
  • Ubiquitin / metabolism
  • Zinc Fingers

Substances

  • PIM2 protein, human
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Tristetraprolin
  • Ubiquitin
  • Protein Serine-Threonine Kinases
  • Proteasome Endopeptidase Complex