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Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7

Narendra Wajapeyee1, Ryan W Serra, Xiaochun Zhu

  • 1Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Cell
|February 13, 2008
PubMed

Insights

Activating the BRAFV600E oncogene triggers IGFBP7 secretion, which paradoxically halts cell growth. This discovery offers new insights into melanoma development and potential therapeutic targets.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Oncogene activation can paradoxically inhibit cell proliferation via senescence or apoptosis.
  • The precise molecular pathways mediating this effect are not fully understood.

Purpose of the Study:

  • To identify genes involved in BRAFV600E-induced proliferation blockade in human primary cells.
  • To elucidate the role of secreted proteins in oncogene-mediated senescence and apoptosis.

Main Methods:

  • Genome-wide RNA-interference screening in human primary fibroblasts and melanocytes.
  • Analysis of BRAF-MEK-ERK signaling pathway.
  • Assessment of apoptosis using BNIP3L upregulation.
  • In vitro testing of recombinant IGFBP7 (rIGFBP7) on melanoma cell lines.
  • In vivo tumor suppression studies in xenografted mice.
  • Immunohistochemical analysis of human skin, nevi, and melanoma samples.

Main Results:

  • 17 genes were identified as essential for BRAFV600E-mediated proliferation blockade.
  • Insulin-like growth factor-binding protein 7 (IGFBP7) plays a crucial role in BRAFV600E-induced senescence and apoptosis.
  • BRAFV600E expression leads to IGFBP7 synthesis and secretion, which inhibits BRAF-MEK-ERK signaling.
  • IGFBP7 upregulates the proapoptotic protein BNIP3L.
  • rIGFBP7 induces apoptosis in BRAFV600E-positive melanoma cells and suppresses tumor growth in vivo.
  • Loss of IGFBP7 expression is implicated as a critical event in melanoma development.

Conclusions:

  • IGFBP7 is a key mediator of BRAFV600E-induced senescence and apoptosis.
  • IGFBP7 acts via autocrine/paracrine mechanisms to inhibit oncogenic signaling and promote cell death.
  • IGFBP7 represents a potential therapeutic target for BRAFV600E-positive melanoma.
  • Loss of IGFBP7 is a significant factor in melanoma genesis.

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