Evidence for proteasome dysfunction in cytotoxicity mediated by anti-Ras intracellular antibodies

Alessio Cardinale, Ilaria Filesi, Sonia Mattei, Silvia Biocca

Research output: Contribution to journalArticlepeer-review


Anti-Ras intracellular antibodies inhibit cell proliferation in vivo by sequestering the antigen and diverting it from its physiological location [Lener, M., Horn, I. R., Cardinale, A., Messina, S., Nielsen, U.B., Rybak, S.M., Hoogenboom, H.R., Cattaneo, A., Biocca, S. (2000) Eur. J. Biochem. 267, 1196-1205]. Here we demonstrate that strongly aggregating single-chain antibody fragments (scFv), binding to Ras, induce apoptosis, and this effect is strictly related to the antibody-mediated aggregation of p21Ras. Proteasomes are quickly recruited to the newly formed aggregates, and their activity is strongly inhibited. This leads to the formation of aggresome-like structures, which become evident in the vast majority of apoptotic cells. A combination of anti-Ras scFv fragments with a nontoxic concentration of the proteasome inhibitor, lactacystin, markedly increases proteasome dysfunction and apoptosis. The dominant-negative H-ras (N17-H-ras), which is mostly soluble and does not induce aggresome formation or inhibit proteasome activity, only affects cell viability slightly. Together, these observations suggest a mechanism linking antibody-mediated Ras aggregation, impairment of the ubiquitin-proteasome system, and cytotoxicity.

Original languageEnglish
Pages (from-to)3389-3397
Number of pages9
JournalEuropean Journal of Biochemistry
Issue number16
Publication statusPublished - Aug 2003


  • Aggresome
  • Anti-p21Ras
  • Apoptosis
  • Proteasome
  • scFv fragment

ASJC Scopus subject areas

  • Biochemistry


Dive into the research topics of 'Evidence for proteasome dysfunction in cytotoxicity mediated by anti-Ras intracellular antibodies'. Together they form a unique fingerprint.

Cite this