TIMP-1 inhibits apoptosis in breast carcinoma cells via a pathway involving pertussis toxin-sensitive G protein and c-Src

Seo Jin Lee, Ho Jung Yoo, Yun Soo Bae, Hwa Jung Kim, Seung Taek Lee

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63 Scopus citations


In addition to inhibiting matrix metalloproteinases, tissue inhibitor of metalloproteinase-1 (TIMP-1) is involved in the regulation of cell growth and survival. To determine its mechanism of action, we investigated effects of TIMP-1 on cell proliferation and survival and signaling pathways induced by TIMP-1 in the human breast carcinoma T-47D cell line. Treatment of T-47D cells with TIMP-1 strongly inhibited apoptosis induced by serum deprivation, but did not affect cell proliferation. TIMP-1 induced phosphorylation of Akt and extracellular signal-regulated protein kinases (ERKs), but pertussis toxin and specific inhibitors of Src family tyrosine kinases, protein tyrosine kinases, and phosphatidylinositol-3 kinase (PI3 kinase) blocked the ability of TIMP-1 to activate Akt and ERKs as well as the anti-apoptotic effect of TIMP-1. We found that TIMP-1 enhanced the kinase activities of c-Src and PI3 kinase and that this enhancement was inhibited by pertussis toxin. Inhibition of ERK activation, however, resulted in a slight decrease of the TIMP-1-induced anti-apoptotic effect. These findings demonstrate that the ability of TIMP-1 to inhibit apoptosis in T-47D cells is mediated by the sequential activation of pertussis toxin-sensitive G protein, c-Src, PI3 kinase, and Akt.

Original languageEnglish
Pages (from-to)1196-1201
Number of pages6
JournalBiochemical and Biophysical Research Communications
Issue number4
StatePublished - 26 Dec 2003

Bibliographical note

Funding Information:
This work was supported by grants from the NRL Program of MOST NRDP, MOST/KOSEF through PNRC at Yonsei University, and the Brain Korea 21 Project. Seo-Jin Lee is a pre-doctoral fellow supported by KRF.


  • Apoptosis
  • Breast cancer
  • Pertussis toxin
  • Signaling pathway
  • TIMP-1
  • c-Src


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