Abstract
We have previously described a novel mechanism of p53 dysfunction, characterized by repression of mRNA and protein expression effectively leading to functional inactivation of wt p53 in SW-1736 human anaplastic thyroid cancer cells (pseudo-null p53). Here we demonstrated that treatment of SW-1736 cells with sub-cytotoxic concentrations of FR901228, a histone deacetylase (HDAC) inhibitor, results in marked induction of p53 mRNA and protein. The p53 induced by FR901228 was functional as evidenced by mdm-2 and p21 transactivation, and its further accumulation following DNA damage by doxorubicin. Furthermore, pretreatment with FR901228 sensitized SW-1736 cells to doxorubicin. This study validates the concept of pseudo-null p53, as a mechanism of p53 inactivation, and demonstrates that pseudo-null p53 can be rescued pharmacologically.
MeSH terms
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Antibiotics, Antineoplastic / pharmacology*
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Antineoplastic Agents / pharmacology
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Carcinoma / drug therapy*
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Carcinoma / pathology
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / metabolism
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DNA Damage / drug effects
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DNA Primers / chemistry
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Depsipeptides*
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Doxorubicin / pharmacology
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Drug Resistance, Neoplasm
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Gene Expression Regulation, Neoplastic / drug effects
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Histone Deacetylase Inhibitors*
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Humans
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Nuclear Proteins*
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Peptides, Cyclic / pharmacology*
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Polymerase Chain Reaction
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-mdm2
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism
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Thyroid Neoplasms / drug therapy*
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Thyroid Neoplasms / metabolism
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Thyroid Neoplasms / pathology
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Transcriptional Activation
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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Tumor Cells, Cultured / pathology
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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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Antineoplastic Agents
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA Primers
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Depsipeptides
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Histone Deacetylase Inhibitors
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Nuclear Proteins
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Peptides, Cyclic
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Proto-Oncogene Proteins
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RNA, Messenger
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RNA, Neoplasm
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Tumor Suppressor Protein p53
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Doxorubicin
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romidepsin
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2