Regulation of expression of BIK proapoptotic protein in human breast cancer cells : p53-dependent induction of BIK mRNA by fulvestrant and proteasomal degradation of BIK protein

Induction of mRNA for BIK proapoptotic protein by doxorubicin or gamma-irradiation requires the DNA-binding transcription factor activity of p53. In MCF7 cells, pure antiestrogen fulvestrant also induces BIK mRNA and apoptosis. Here, we provide evidence that, in contrast to doxorubicin or gamma-irra...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2006-10, Vol.66 (20), p.10153-10161
Main Authors: HUR, Jingyung, BELL, Daphne W, DEAN, Kathleen L, COSER, Kathryn R, HILARIO, Pablo C, OKIMOTO, Ross A, TOBEY, Erica M, SMITH, Shannon L, ISSELBACHER, Kurt J, SHIODA, Toshi
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - pharmacology
Antineoplastic Agents, Hormonal - pharmacology
Apoptosis Regulatory Proteins - biosynthesis
Apoptosis Regulatory Proteins - genetics
Biological and medical sciences
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Cell Line, Tumor
Doxorubicin - pharmacology
Estradiol - analogs & derivatives
Estradiol - pharmacology
Gamma Rays
Gene Expression Regulation, Neoplastic - drug effects
Gene Expression Regulation, Neoplastic - radiation effects
Gynecology. Andrology. Obstetrics
Humans
Leupeptins - pharmacology
Mammary gland diseases
Medical sciences
Membrane Proteins - biosynthesis
Membrane Proteins - genetics
Pharmacology. Drug treatments
Promoter Regions, Genetic
Proteasome Endopeptidase Complex - metabolism
Proteasome Inhibitors
Receptors, Estrogen - biosynthesis
RNA, Messenger - biosynthesis
RNA, Messenger - genetics
Transcription, Genetic - drug effects
Transcription, Genetic - radiation effects
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Tumor Suppressor Protein p53 - physiology
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Summary:Induction of mRNA for BIK proapoptotic protein by doxorubicin or gamma-irradiation requires the DNA-binding transcription factor activity of p53. In MCF7 cells, pure antiestrogen fulvestrant also induces BIK mRNA and apoptosis. Here, we provide evidence that, in contrast to doxorubicin or gamma-irradiation, fulvestrant induction of BIK mRNA is not a direct effect of the transcriptional activity of p53, although p53 is necessary for this induction. It is known that p53 up-regulated modulator of apoptosis (PUMA) mRNA is induced directly by the transcriptional activity of p53. Whereas gamma-irradiation induced both BIK and PUMA mRNA, only BIK mRNA was induced by fulvestrant. Whereas both fulvestrant and doxorubicin induced BIK mRNA, only doxorubicin enhanced the DNA-binding activity of p53 and induced PUMA mRNA. Small interfering RNA (siRNA) suppression of p53 expression as well as overexpression of dominant-negative p53 effectively inhibited the fulvestrant induction of BIK mRNA, protein, and apoptosis. Transcriptional activity of a 2-kb BIK promoter, which contained an incomplete p53-binding sequence, was not affected by fulvestrant when tested by reporter assay. Fulvestrant neither affected the stability of the BIK mRNA transcripts. Interestingly, other human breast cancer cells, such as ZR75-1, constitutively expressed BIK mRNA even without fulvestrant. In these cells, however, BIK protein seemed to be rapidly degraded by proteasome, and siRNA suppression of BIK in ZR75-1 cells inhibited apoptosis induced by MG132 proteasome inhibitor. These results suggest that expression of BIK in human breast cancer cells is regulated at the mRNA level by a mechanism involving a nontranscriptional activity of p53 and by proteasomal degradation of BIK protein.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-05-3696