PMID- 11375890
OWN - NLM
STAT- MEDLINE
DCOM- 20010621
LR  - 20190513
IS  - 0143-3334 (Print)
IS  - 0143-3334 (Linking)
VI  - 22
IP  - 6
DP  - 2001 Jun
TI  - Inhibition of HIF-1- and wild-type p53-stimulated transcription by codon Arg175 
      p53 mutants with selective loss of functions.
PG  - 861-7
AB  - Overexpression of ectopic mutant p53 represses wild-type p53-stimulated 
      transcription, known as a dominant negative effect. On the other hand, 
      overexpression of wild-type p53 can repress transcription stimulated by several 
      transcription factors, including hypoxia-inducible factor-1 (HIF-1). Using a 
      panel of well-characterized Arg175 p53 mutants we found that only mutants 
      (Tyr175, Trp175, Asp175 and Phe175) which have completely lost their ability to 
      transactivate repress wild-type p53-stimulated Bax, p21 and PG13 promoter 
      constructs. In contrast, Asn175, Gln175, Leu175 and Pro175 mutants which 
      partially retained transactivating functions did not exert dominant negative 
      effects against PG13 and p21 promoter constructs. However, these latter mutants 
      failed to activate Bax and, instead, exerted a dominant negative effect on a 
      Bax-Luc promoter construct. We conclude that a dominant negative effect is 
      promoter selective as a consequence of selective loss of transactivating 
      function. Albeit less potent than wild-type p53, all Arg175 p53 mutants retained 
      partial ability to repress HIF-1-stimulated transcription. We propose that 
      transrepression and the dominant negative effect have similar mechanisms and may 
      involve competition with transcription factors (wild-type p53, HIF-1, etc.) for 
      cofactors such as p300. Thus, a p53(22/23) mutant, which is deficient in p300 
      binding, did not exert dominant negative effects. Like transrepression, the 
      dominant negative effect required overexpression of mutant p53 and, therefore, is 
      not dominant. In the presence of a wild-type p53 allele, levels of endogenous 
      mutant p53 protein were low in heterozygous cells. Endogenous mutant p53 became 
      overexpressed only after loss of the second p53 allele. Therefore, endogenous 
      mutant p53s are unable to display a dominant negative effect. This explains why 
      loss of the second p53 allele is required to eliminate p53 functions in cancer 
      cells.
FAU - Blagosklonny, M V
AU  - Blagosklonny MV
AD  - Medicine Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. 
      mikhailb@box-m.nih.gov
FAU - Giannakakou, P
AU  - Giannakakou P
FAU - Romanova, L Y
AU  - Romanova LY
FAU - Ryan, K M
AU  - Ryan KM
FAU - Vousden, K H
AU  - Vousden KH
FAU - Fojo, T
AU  - Fojo T
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (BAX protein, human)
RN  - 0 (CDKN1A protein, human)
RN  - 0 (Codon)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (Cyclins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (bcl-2-Associated X Protein)
RN  - 94ZLA3W45F (Arginine)
SB  - IM
MH  - Arginine/genetics
MH  - Binding Sites
MH  - Breast Neoplasms/genetics
MH  - Codon/genetics
MH  - Consensus Sequence
MH  - Cyclin-Dependent Kinase Inhibitor p21
MH  - Cyclins/genetics
MH  - DNA-Binding Proteins/*antagonists & inhibitors/genetics/physiology
MH  - Female
MH  - Humans
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Male
MH  - *Mutation
MH  - Nuclear Proteins/*antagonists & inhibitors/genetics/physiology
MH  - Promoter Regions, Genetic
MH  - Prostatic Neoplasms/genetics
MH  - Proto-Oncogene Proteins/genetics
MH  - *Proto-Oncogene Proteins c-bcl-2
MH  - Substrate Specificity
MH  - *Transcription Factors
MH  - Transcription, Genetic
MH  - Transcriptional Activation/*physiology
MH  - Tumor Cells, Cultured
MH  - Tumor Suppressor Protein p53/*antagonists & inhibitors/genetics/physiology
MH  - bcl-2-Associated X Protein
EDAT- 2001/05/29 10:00
MHDA- 2001/06/22 10:01
CRDT- 2001/05/29 10:00
PHST- 2001/05/29 10:00 [pubmed]
PHST- 2001/06/22 10:01 [medline]
PHST- 2001/05/29 10:00 [entrez]
AID - 10.1093/carcin/22.6.861 [doi]
PST - ppublish
SO  - Carcinogenesis. 2001 Jun;22(6):861-7. doi: 10.1093/carcin/22.6.861.