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Peptides from the amino terminal mdm-2-binding domain of p53, designed from conformational analysis, are selectively cytotoxic to transformed cells.

Authors
Kanovsky-M; Raffo-A; Drew-L; Rosal-R; Do-T; Friedman-FK; Rubinstein-P; Visser-J; Robinson-R; Brandt-Rauf-PW; Michl-J; Fine-RL; Pincus-MR
Source
Proc Natl Acad Sci U.S.A. 2001 Oct; 98(22):12438-12443
NIOSHTIC No.
20042212
Abstract
We have synthesized three peptides from the mdm-2 binding domain of human p53, residues 12-26 (PPLSQETFSDLWKLL), residues 12-20, and 17-26. To enable transport of the peptides across the cell membrane and at the same time to maximize the active mdm-2 binding alpha-helical conformation for these peptides, each was attached at its carboxyl terminus to the penetratin sequence, KKWKMRRNQFWVKVQRG, that contains many positively charged residues that stabilize an alpha-helix when present on its carboxyl terminal end. All three peptides were cytotoxic to human cancer cells in culture, whereas a control, unrelated peptide attached to the same penetratin sequence had no effect on these cell lines. The same three cytotoxic peptides had no effect on the growth of normal cells, including human cord blood-derived stem cells. These peptides were as effective in causing cell death in p53-null cancer cells as in those having mutant or normal p53. Peptide-induced cell death is not accompanied by expression of apoptosis-associated proteins such as Bax and waf(p21). Based on these findings, we conclude that the antiproliferative effects of these p53-derived peptides are not completely dependent on p53 activity and may prove useful as general anticancer agents.
Keywords
Peptides; Cell-cultures; Cell-biology; Cell-function; Cellular-function; Cytotoxic-effects; Cancer; Blood-cells
CODEN
PNASA6
Publication Date
20011023
Document Type
Journal Article
Email Address
pincusm@vax.cs.hscsyr.edu
Funding Type
Grant
Fiscal Year
2002
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-004192
Issue of Publication
22
ISSN
0027-8424
Source Name
Proceedings of the National Academy of Sciences of the United States of America
State
NY; MD
Performing Organization
Department of Environmental Health Sciences, The Mailman School of Public Health, Columbia University, New York, New York
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