A novel intracellular peptide derived from g1/s cyclin d2 induces cell death.
Intracellular peptides are constantly produced by the ubiquitin-proteasome system, and many are probably functional. Here, the peptide WELVVLGKL (pep5) from G1/S-specific cyclin D2 showed a 2-fold increase during the S phase of HeLa cell cycle. pep5 (25-100 μm) 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 p38α and -γ, 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.
From the Departments of Pharmacology and.
Christiane B
CB
de Araujo
the Department of Biochemistry, Support Center for Research in Proteolysis and Cell Signaling (NAPPS), Institute of Chemistry, University of São Paulo, 05508-000, São Paulo, SP, Brazil.
Lilian C
LC
Russo
From the Departments of Pharmacology and.
Leandro M
LM
Castro
the Department of Biochemistry, Support Center for Research in Proteolysis and Cell Signaling (NAPPS), Institute of Chemistry, University of São Paulo, 05508-000, São Paulo, SP, Brazil.
Fábio L
FL
Forti
From the Departments of Pharmacology and.
Elisabete R
ER
do Monte
the Special Laboratory of Applied Toxinology (LETA), Center of Toxins, Immune Response, and Cell Signaling (CETICS), Butantan Institute, 05503-000, São Paulo, SP, Brazil, and.
Vanessa
V
Rioli
the Institute of Chemistry, State University of Campinas, 13083-862, Campinas, SP, Brazil.
Fabio C
FC
Gozzo
Cell Biology and Development, Support Center for Research in Proteolysis and Cell Signaling (NAPPS), Biomedical Science Institute, University of São Paulo, São Paulo, 05508-000, SP, Brazil.
Alison
A
Colquhoun
From the Departments of Pharmacology and eferro@usp.br.
Emer S
ES
Ferro
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D020816:Amino Acid Motifs; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D056742:Cyclin D2 / Q000737:chemistry / Q000494:pharmacology*; D005909:Glioblastoma / Q000188:drug therapy; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D061986:MCF-7 Cells; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
C503757:2-(1H-indol-3-yl)-3-pentylamino-maleimide; D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D056742:Cyclin D2; D007093:Imidazoles; D007211:Indoles; D008301:Maleimides; D009842:Oligopeptides; D011804:Quinolines; C507699:necrostatin-1; C468548:quinoline-val-asp(OMe)-CH2-OPH
Anticancer Drug; Apoptosis; Cell Cycle; Cell Death; Necrosis (Necrotic Death); Peptides; Proteasome