Abstract
A role of apoptosis (programmed cell death) in tumor formation and growth was investigated by targeting the apoptosis inhibitor survivin in vivo. Expression of a phosphorylation-defective survivin mutant (Thr(34)-->Ala) triggered apoptosis in several human melanoma cell lines and enhanced cell death induced by the chemotherapeutic drug cisplatin in vitro. Conditional expression of survivin Thr(34)-->Ala in YUSAC2 melanoma cells prevented tumor formation upon s.c. injection into CB.17 severe combined immunodeficient-beige mice. When induced in established melanoma tumors, survivin Thr(34)-->Ala inhibited tumor growth by 60-70% and caused increased apoptosis and reduced proliferation of melanoma cells in vivo. Manipulation of the antiapoptotic pathway maintained by survivin may be beneficial for cancer therapy.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Substitution
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Animals
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Antineoplastic Agents, Alkylating / pharmacology*
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Apoptosis / drug effects
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Apoptosis / genetics*
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Blotting, Western
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CDC2 Protein Kinase / metabolism
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Cisplatin / pharmacology*
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Gene Targeting*
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Humans
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Inhibitor of Apoptosis Proteins
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Melanoma / pathology*
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Melanoma, Experimental / genetics
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Melanoma, Experimental / therapy*
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Mice
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Mice, Mutant Strains
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Mice, SCID
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Microtubule-Associated Proteins*
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Mutagenesis, Site-Directed
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Mutation, Missense
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Neoplasm Proteins / physiology*
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Neoplasm Transplantation
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Phosphorylation
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Protein Processing, Post-Translational / genetics
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Proteins / genetics
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Proteins / metabolism
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Proteins / physiology*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / physiology
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Substrate Specificity
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Survivin
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Transfection
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Alkylating
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BIRC5 protein, human
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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Neoplasm Proteins
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Proteins
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Recombinant Fusion Proteins
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Survivin
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CDC2 Protein Kinase
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Cisplatin