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Mechanisms of Cdc48/VCP-mediated cell death: from yeast apoptosis to human disease

Ralf J Braun1, Hans Zischka

  • 1Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Munich-Neuherberg, Germany. r.j.braun@web.de

Biochimica Et Biophysica Acta
|February 21, 2008
PubMed

Insights

The protein Cdc48/VCP has complex roles in cell death, acting as both pro-apoptotic and anti-apoptotic. Its dysfunction is linked to diseases like IBMPFD and cancer.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Cdc48/VCP is an evolutionarily conserved protein vital for cellular processes including protein degradation and membrane fusion.
  • Elevated Cdc48/VCP levels are associated with cancer, while its endogenous levels are implicated in protein deposition diseases.
  • Mutations in Cdc48/VCP cause the multisystem disorder IBMPFD, highlighting its critical role in human health.

Purpose of the Study:

  • To critically compare the mechanisms of Cdc48/VCP-mediated apoptosis in yeast and other species.
  • To elucidate the poorly understood roles of Cdc48/VCP in cell death within various pathological conditions.
  • To understand the dual role of Cdc48/VCP in both decreased and increased incidences of cell death.

Main Methods:

  • Comparative analysis of Cdc48/VCP function in yeast and other species.
  • Review of existing literature on Cdc48/VCP mutations, depletion, and expression levels in relation to cell death.
  • Examination of Cdc48/VCP's involvement in ER stress, oxidative stress, caspase processing, and pro-survival signaling pathways (Akt, NFkappaB).

Main Results:

  • Loss-of-function mutations or depletion of Cdc48/VCP induce ER and oxidative stress, leading to apoptosis.
  • Functional Cdc48/VCP plays a pro-apoptotic role by aiding caspase processing during ER stress.
  • Cdc48/VCP also exhibits an anti-apoptotic function by activating pro-survival pathways like Akt and NFkappaB.

Conclusions:

  • Cdc48/VCP has a multifaceted role in cell death, acting as a key regulator in both apoptotic and anti-apoptotic pathways.
  • The complex involvement of Cdc48/VCP in cell death mechanisms aligns with its diverse roles in various pathophysiological conditions, including cancer and protein deposition diseases.
  • Understanding these dual roles is crucial for deciphering the pathology of diseases associated with Cdc48/VCP dysfunction.

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