The histone deacetylase inhibitor FR901228 (desipeptide) restores expression and function of pseudo-null p53.
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.
Kitazono
Masaki
M
Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Bates
Susan
S
Fok
Patrick
P
Fojo
Tito
T
Blagosklonny
Mikhail V
MV
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D017931:DNA Primers / Q000737:chemistry; D047630:Depsipeptides; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009687:Nuclear Proteins; D010456:Peptides, Cyclic / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017931:DNA Primers; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D009687:Nuclear Proteins; D010456:Peptides, Cyclic; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C087123:romidepsin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2