PMID- 10449408
OWN - NLM
STAT- MEDLINE
DCOM- 19990927
LR  - 20161124
IS  - 0261-4189 (Print)
IS  - 0261-4189 (Linking)
VI  - 18
IP  - 16
DP  - 1999 Aug 16
TI  - Increased apoptosis induction by 121F mutant p53.
PG  - 4424-37
AB  - p53 mutants in tumours have a reduced affinity for DNA and a reduced ability to
      induce apoptosis. We describe a mutant with the opposite phenotype, an increased 
      affinity for some p53-binding sites and an increased ability to induce apoptosis.
      The apoptotic function requires transcription activation by p53. The mutant has
      an altered sequence specificity and selectively fails to activate MDM2
      transcription. Loss of MDM2 feedback results in overexpression of the mutant, but
      the mutant kills better than wild-type p53 even in MDM2-null cells. Thus the
      apoptotic phenotype is due to a combination of decreased MDM2 feedback control
      and increased or unbalanced expression of other apoptosis-inducing p53 target
      genes. To identify these genes, DNA chips were screened using RNA from cells
      expressing the apoptosis-inducing mutant, 121F, and a sequence-specificity mutant
      with the reciprocal phenotype, 277R. Two potential new mediators of p53-dependent
      apoptosis were identified, Rad and PIR121, which are induced better by 121F than 
      wild-type p53 and not induced by 277R. The 121F mutant kills untransformed
      MDM2-null but not wild-type mouse embryo fibroblasts and kills tumour cells
      irrespective of p53 status. It may thus expand the range of tumours which can be 
      treated by p53 gene therapy.
FAU - Saller, E
AU  - Saller E
AD  - Swiss Institute for Experimental Cancer Research (ISREC), CH-1066 Epalinges,
      Switzerland.
FAU - Tom, E
AU  - Tom E
FAU - Brunori, M
AU  - Brunori M
FAU - Otter, M
AU  - Otter M
FAU - Estreicher, A
AU  - Estreicher A
FAU - Mack, D H
AU  - Mack DH
FAU - Iggo, R
AU  - Iggo R
LA  - eng
SI  - GENBANK/AF160973
SI  - GENBANK/AF162472
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (CDKN1A protein, human)
RN  - 0 (Cdkn1a protein, mouse)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (Cyclins)
RN  - 0 (DNA, Complementary)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 2.3.2.27 (MDM2 protein, human)
RN  - EC 2.3.2.27 (Mdm2 protein, mouse)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
SB  - IM
MH  - Animals
MH  - *Apoptosis
MH  - Base Sequence
MH  - Cyclin-Dependent Kinase Inhibitor p21
MH  - Cyclins/metabolism
MH  - DNA, Complementary
MH  - Gene Expression Regulation
MH  - Humans
MH  - Mice
MH  - Molecular Sequence Data
MH  - Mutagenesis
MH  - *Nuclear Proteins
MH  - Phenotype
MH  - Promoter Regions, Genetic
MH  - Proto-Oncogene Proteins/genetics
MH  - Proto-Oncogene Proteins c-mdm2
MH  - Tumor Cells, Cultured
MH  - Tumor Suppressor Protein p53/genetics/*metabolism
PMC - PMC1171517
EDAT- 1999/08/17 00:00
MHDA- 1999/08/17 00:01
CRDT- 1999/08/17 00:00
PHST- 1999/08/17 00:00 [pubmed]
PHST- 1999/08/17 00:01 [medline]
PHST- 1999/08/17 00:00 [entrez]
AID - 10.1093/emboj/18.16.4424 [doi]
PST - ppublish
SO  - EMBO J. 1999 Aug 16;18(16):4424-37. doi: 10.1093/emboj/18.16.4424.