Abstract
Stathmin, a microtubule regulatory protein, is overexpressed in many cancers and required for survival of several cancer lines. In a study of breast cancer cell lines(1) proposed that stathmin is required for survival of cells lacking p53, but this hypothesis was not tested directly. Here we tested their hypothesis by examining cell survival in cells depleted of stathmin, p53 or both proteins. Comparing HCT116 colon cancer cell lines differing in TP53 genotype, stathmin depletion resulted in significant death only in cells lacking p53. As a second experimental system, we compared the effects of stathmin depletion from HeLa cells, which normally lack detectable levels of p53 due to expression of the HPV E6 protein. Stathmin depletion caused a large percentage of HeLa cells to die. Restoring p53, by depletion of HPV E6, rescued HeLa cells from stathmin-depletion induced death. Cleaved PARP was detected in HCT116(p53-/-) cells depleted of stathmin and cell death in stathmin-depleted HeLa cells was blocked by the caspase inhibitor Z-VAD-FMK, consistent with apoptotic death. The stathmin-dependent survival of cells lacking p53 was not confined to cancerous cells because both proteins were required for survival of normal human fibroblasts. In HCT116 and HeLa cells, depletion of both stathmin and p53 leads to a cell cycle delay through G(2). Our results demonstrate that stathmin is required for cell survival in cells lacking p53, suggesting that stathmin depletion could be used therapeutically to induce apoptosis in tumors without functional p53.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibiotics, Antineoplastic / pharmacology
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Apoptosis / drug effects
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Blotting, Western
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Cell Proliferation / drug effects
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Cell Survival
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Cells, Cultured
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Colonic Neoplasms / metabolism*
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Colonic Neoplasms / pathology*
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Cytoskeletal Proteins / antagonists & inhibitors
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism
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Doxorubicin / pharmacology
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Fibroblasts / cytology*
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Fibroblasts / metabolism*
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Fluorescent Antibody Technique
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Genes, Tumor Suppressor
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Humans
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Muscle Proteins / antagonists & inhibitors
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Muscle Proteins / genetics
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Muscle Proteins / metabolism
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Oncogene Proteins, Viral / antagonists & inhibitors
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Oncogene Proteins, Viral / genetics
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Oncogene Proteins, Viral / metabolism
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / metabolism
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RNA, Messenger / genetics
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RNA, Small Interfering / pharmacology
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Stathmin / physiology*
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Tumor Suppressor Protein p53 / antagonists & inhibitors
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Antibiotics, Antineoplastic
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Cytoskeletal Proteins
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E6 protein, Human papillomavirus type 16
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Muscle Proteins
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Oncogene Proteins, Viral
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RNA, Messenger
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RNA, Small Interfering
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Repressor Proteins
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SMTN protein, human
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Stathmin
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TP53 protein, human
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Tumor Suppressor Protein p53
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Doxorubicin
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Poly(ADP-ribose) Polymerases