Prohibitin regulates TGF-β induced apoptosis as a downstream effector of Smad-dependent and -independent signaling

Brian Zhu, Jianjun Zhai, Haining Zhu, Natasha Kyprianou

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

BACKGROUND. Prohibitin (PHB), a protein located on the inner mitochondrial membrane and nuclei, is an intracellular effector of transforming growth factor-β (TGF-β) signaling in prostate cancer cells. This study investigated the involvement of PHB in the apoptosis and survival outcomes of human prostate cancer cell to TGF-β. shRNA PHB loss of function in prostate cancer cells led to enhanced apoptotic response to TGF-β via Smad-dependent mechanism. METHOD. TGF-β activation of Raf-Erk intracellular signaling, led to PHB phosphorylation, decreased inner mitochondrial permeability, and increased cell survival. Calcein-based immunofluorescence studies revealed the functional involvement of PHB in maintaining inner mitochondrial membrane permeability as an integral component of TGF-β induced apoptosis in prostate cancer cells. RESULTS. These finding indicates that induction of TGF-β apoptosis is mediated by Smad-dependent and Smad-independent signaling (MAPK) converging at PHB as a downstream effector regulating inner mitochondrial permeability. Putative PHB associated proteins were identified by subjecting TGF-β treated cells to immunoprecipitation with anti-PHB, and mass spectrometry. A screen for the kinase specific phosphorylation sites of PHB revealed three protein kinase (PKC) binding sites. CONCLUSION. Our results demonstrate that TGF-β led to upregulation of the PKC inhibitor 14-3-3 protein and promoted its association with PHB, while PHB association with PKC-δ, was inhibited by the MEK1 inhibitor, documenting a critical interdependence between the MEK-ERK signaling and prohibitin phosphorylation. These findings suggest a dual role for PHB as a downstream determinant of the cellular response to TGF-β via Smad-dependent pathway (apoptosis) and MAPK intracellular signaling (survival).

Original languageEnglish (US)
Pages (from-to)17-26
Number of pages10
JournalProstate
Volume70
Issue number1
DOIs
StatePublished - Jan 1 2010
Externally publishedYes

Keywords

  • Apoptosis
  • MAPK signaling
  • Prohibitin
  • Prostate cancer
  • Smads
  • TGF-β

ASJC Scopus subject areas

  • Oncology
  • Urology

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