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The In Vivo DNA Binding Properties of Wild-Type and Mutant p53 Proteins in Mammary Cell Lines During the Course of Cell Cycle.

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Annual rept. 30 Jun 95-1 Jul 96,

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Using a pair of murine cell lines, one lacking p53 and a derivative cell line containing temperature sensitive p53 val 135 which is wt at 32 deg C, we have identified the sequences in the mdm2 promoter protected by protein in the nuclear chromatin after temperature shifting. Each putative p53 response element RE in the ts ps3 containing cell line is protected over its downstream half by 4 hours at 32 deg C with further changes in protection resulting by 24 hours, while the same sequence is unprotected in the cell line without p53. Thus demonstrating dynamic p53 dependent DNA-protein interactions. We compared the transcription activity from three reporter plasmids containing either 16p53 REs, the mdm2 promoter or the HIV-LTR in breast cancer cell lines ZR75-1 wtp53 -, MDA-MB-468 His273 p53 and MDA-MB-157 no p53. In ZR75-1 the 16 p53 REs showed the highest activity, suggesting that wild-type p53 in these cells can function however DNA damaging drugs are unable to stabilize the p53 present, suggesting normal p53 activity is impaired. In MDA-MB-468 the HIV-LTR construct shows the highest activity while in MDA-MB-157 the activity of all three constructs is approximately the same. This suggests that His273 p53 in MDA-MB-468 is able to activate transcription from the HIV-LTR.

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  • Medicine and Medical Research

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