Tumor-promoting phorbol ester transiently down-modulates the p53 level and blocks the cell cycle
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Tumor-promoting phorbol ester transiently down-modulates the p53 level and blocks the cell cycle. / Skouv, J.; Jensen, P O; Forchhammer, J; Larsen, J K; Lund, L R.
In: Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research, Vol. 5, No. 3, 03.1994, p. 329-40.Research output: Contribution to journal › Journal article › peer-review
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T1 - Tumor-promoting phorbol ester transiently down-modulates the p53 level and blocks the cell cycle
AU - Skouv, J.
AU - Jensen, P O
AU - Forchhammer, J
AU - Larsen, J K
AU - Lund, L R
PY - 1994/3
Y1 - 1994/3
N2 - Activation of the protein kinase C signaling pathway by tumor-promoting phorbol esters, such as 4 beta-phorbol 12-myristate 13-acetate (PMA), induced a decrease in the level of p53 mRNA in several serum-starved human cell lines. Also, the tumor-promoting phosphatase inhibitor okadaic acid induced a decrease in the p53 mRNA level in the cell lines. Normal diploid as well as various tumor cell lines were tested. Two tumor cell lines, HeLa and A549, both containing the wild-type p53 gene, but very different levels of p53 protein, were studied in detail. In both cell lines, the level of p53 mRNA was minimal after 9 h of exposure to PMA. After approximately 120 h, the p53 mRNA level was similar to the pretreatment level. PMA induced a similar transient decrease in the level of p53 protein in the A549 cell line. The decrease in the p53 mRNA level could not be explained by changes in the transcriptional rate or the p53 mRNA stability. The protein synthesis inhibitor cycloheximide completely abolished the PMA-induced down-modulation of the p53 mRNA, suggesting that a short-lived protein was involved in the down-modulation. Flow cytometric cell cycle analysis showed that the phorbol ester treatment induced a block in the late G1 phase. The blockage was transient, and its duration correlated with the level of p53 protein in the two cell lines. We propose that the protein kinase C-catalyzed phosphorylation of p53 may be a key event in the down-modulation of p53 expression as well as in the induced blockage of the cell cycle.
AB - Activation of the protein kinase C signaling pathway by tumor-promoting phorbol esters, such as 4 beta-phorbol 12-myristate 13-acetate (PMA), induced a decrease in the level of p53 mRNA in several serum-starved human cell lines. Also, the tumor-promoting phosphatase inhibitor okadaic acid induced a decrease in the p53 mRNA level in the cell lines. Normal diploid as well as various tumor cell lines were tested. Two tumor cell lines, HeLa and A549, both containing the wild-type p53 gene, but very different levels of p53 protein, were studied in detail. In both cell lines, the level of p53 mRNA was minimal after 9 h of exposure to PMA. After approximately 120 h, the p53 mRNA level was similar to the pretreatment level. PMA induced a similar transient decrease in the level of p53 protein in the A549 cell line. The decrease in the p53 mRNA level could not be explained by changes in the transcriptional rate or the p53 mRNA stability. The protein synthesis inhibitor cycloheximide completely abolished the PMA-induced down-modulation of the p53 mRNA, suggesting that a short-lived protein was involved in the down-modulation. Flow cytometric cell cycle analysis showed that the phorbol ester treatment induced a block in the late G1 phase. The blockage was transient, and its duration correlated with the level of p53 protein in the two cell lines. We propose that the protein kinase C-catalyzed phosphorylation of p53 may be a key event in the down-modulation of p53 expression as well as in the induced blockage of the cell cycle.
KW - Cell Cycle
KW - Cycloheximide
KW - Down-Regulation
KW - Ethers, Cyclic
KW - Half-Life
KW - Humans
KW - Okadaic Acid
KW - Protein Kinase C
KW - RNA, Messenger
KW - Tetradecanoylphorbol Acetate
KW - Time Factors
KW - Transcription, Genetic
KW - Tumor Cells, Cultured
KW - Tumor Suppressor Protein p53
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
M3 - Journal article
C2 - 8018565
VL - 5
SP - 329
EP - 340
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
SN - 1044-9523
IS - 3
ER -
ID: 181873979