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RASSF7 negatively regulates pro-apoptotic JNK signaling by inhibiting the activity of phosphorylated-MKK7

S Takahashi1, A Ebihara, H Kajiho

  • 1Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.

Cell Death and Differentiation
|February 1, 2011
PubMed

Insights

Ras-association domain family 7 (RASSF7) protein regulates apoptosis by interacting with N-Ras to inhibit stress-induced c-Jun N-terminal kinase (JNK) signaling. RASSF7 promotes cell survival initially but is degraded under prolonged stress, allowing apoptosis.

Area of Science:

  • Cell biology
  • Molecular mechanisms of apoptosis
  • Signal transduction pathways

Background:

  • Ras-association domain family (RASSF) proteins are involved in apoptosis and cell cycle regulation.
  • The precise mechanisms by which RASSF proteins, particularly RASSF7, modulate these processes remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which RASSF7 influences apoptosis and cell cycling.
  • To investigate the interaction of RASSF7 with N-Ras and its role in regulating c-Jun N-terminal kinase (JNK) signaling.

Main Methods:

  • RNA interference (RNAi) knockdown to deplete RASSF7 and N-Ras.
  • Analysis of mitogen-activated protein kinase kinase 7 (MKK7) phosphorylation and JNK activation.
  • Assessment of apoptosis in response to stress stimuli.
  • Investigation of RASSF7 protein stability and degradation via the ubiquitin-proteasome pathway.

Main Results:

  • RASSF7 interacts with N-Ras and mitogen-activated protein kinase kinase 7 (MKK7) to negatively regulate JNK signaling.
  • Depletion of RASSF7 or N-Ras enhances stress-induced JNK activation and apoptosis.
  • RASSF7 binding to MKK7 promotes MKK7 phosphorylation but inhibits JNK activation.
  • RASSF7's anti-apoptotic function requires its RA domain for N-Ras interaction and is transient, as RASSF7 is degraded under prolonged stress.

Conclusions:

  • RASSF7, in conjunction with N-Ras, acts as a temporary, stress-sensitive regulator of apoptosis.
  • Initially, the RASSF7/N-Ras complex inhibits the MKK7/JNK pathway, promoting cell survival.
  • Prolonged stress leads to RASSF7 degradation, permitting cell death signaling and potentially explaining the link between elevated RASSF7 and tumorigenesis.

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