Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 24, Pages 16711-16726Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.537118
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Funding
- Brazilian National Research Council (CNPq) [559698/2009-7]
- Pro-Reitoria de Pesquisa, University of Sao Paulo, through the Support Center for Research in Proteolysis and Cell Signaling (NAPPS) [2012.1.17607.1.2]
- CAPES
- CNPq
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Intracellular peptides are constantly produced by the ubiquitin-proteasome system, and many are probably functional. Here, the peptide WELVVLGKL (pep5) from G(1)/S-specific cyclin D2 showed a 2-fold increase during the S phase of HeLa cell cycle. pep5 (25-100 mu M) induced cell death in several tumor cells only when it was fused to a cell-penetrating peptide (pep5-cpp), suggesting its intracellular function. In vivo, pep5-cpp reduced the volume of the rat C6 glioblastoma by almost 50%. The tryptophan at the N terminus of pep5 is essential for its cell death activity, and N terminus acetylation reduced the potency of pep5-cpp. WELVVL is the minimal active sequence of pep5, whereas Leu-Ala substitutions totally abolished pep5 cell death activity. Findings from the initial characterization of the cell death/signaling mechanism of pep5 include caspase 3/7 and 9 activation, inhibition of Akt2 phosphorylation, activation of p38 alpha and -gamma, and inhibition of proteasome activity. Further pharmacological analyses suggest that pep5 can trigger cell death by distinctive pathways, which can be blocked by IM-54 or a combination of necrostatin-1 and q-VD-OPh. These data further support the biological and pharmacological potential of intracellular peptides.
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