Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles

Yin, Yuxin; Tainsky, Michael A.; Bischoff, Farideh Z.; Strong, Louise C.; Wahl, Geoffrey M.

doi:10.1016/0092-8674(92)90244-7

Cited by 1,040 publications

(607 citation statements)

References 53 publications

Supporting

Mentioning

567

Contrasting

Unclassified

Order By: Relevance

“…Observations showing that mutations or de®ciency of p53 can promote genetic instability, including gene ampli®cations, argue in favour of the participation of p53 in this regulation (Donehower et al, 1992(Donehower et al, , 1995Livingstone et al, 1992). Expression of wild-type p53 in cells containing mutant p53 alleles also reduced the frequency of gene ampli®cation (Yin et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

A functional analysis of p53 during early development of xenopus laevis

et al. 1997

View full text Add to dashboard Cite

p53 is a nuclear protein that acts like a tumor suppressor and is involved in regulation of cellular growth. In Xenopus, the p53 protein is highly expressed during oogenesis and is strictly cytoplasmic in the oocyte. We have analysed its participation in DNA replication and transcription during early development, using the egg and oocyte as model-systems. The injection of sperm nuclei into Xenopus eggs is followed by DNA replication and mitotic events. We show that the endogenous p53 enters the nuclei and moves through a series of discrete subnuclear loci whose distribution is S-phase speci®c. A speci®c peripheral nuclear localization of p53 is observed before entry into S-phase, followed by an internal localization which is strictly dependent on ongoing DNA synthesis. At no stage in the cell cycle, however, did we observe any co-localization with RPA or PCNA, which were used as initiation or elongation markers for DNA replication. We also show that injection into the nucleus of the oocyte of small amounts of either Xenopus or human p53 ± less than 10% of the cytoplasmic storage ± is su cient to block RNA polymerase IIdependent transcription from a coinjected TATA-boxcontaining reporter plasmid. Transcription is rescued by microinjection of the TATA-box binding protein (TBP), suggesting that nuclear exclusion of p53 during oogenesis may be necessary for transcription of maternal genes. These characteristics are discussed in relation to the regulation of nuclear activities during early embryogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

A functional analysis of p53 during early development of xenopus laevis

et al. 1997

View full text Add to dashboard Cite

show abstract

“…Alternatively, cells with an aneuploid karyotype that have acquired supernumerary chromosomes carrying the gene in question might have been selected. As the ®rst mentioned process requires interference with p53 (Livingstone et al, 1992;Yin et al, 1992;Nelson and Kastan, 1994) and as PyLT is known not to combat with this protein, we thought it more likely that the latter mechanisms, aneuploidization, is responsible for the appearance of PALA resistant cells in response to the activity of PyLT. We, therefore, determined the chromosome number of several PALA resistant clones and compared it with that of normal REF52 cells, as well as with that of cells transfected with the neo gene only or with mutated PyLT.…”

Section: Characterization Of Pala Resistant Ref52 Cellsmentioning

confidence: 99%

“…The tumorsuppressor protein p53 has been shown to play an important role in the checkpoint control elicited by DNA damage (Yin et al, 1992;Livingstone et al, 1992; see also the review by Cox and Lane, 1995) or by a shortage of DNA synthesis precursors (Linke et al, 1996). The latter situation arises, for instance, after addition of phosphonoacetyl-L-aspartate (PALA) to cell cultures.…”

Section: Introductionmentioning

confidence: 99%

Polyomavirus large T antigen-dependent DNA amplification

et al. 1997

View full text Add to dashboard Cite

DNA ampli®cation is a readily measurable indicator for genome destabilization. Contrary to normal senescing cells, those of most immortal or transformed cell lines are karyotypically unstable and permissive for ampli®ca-tion. Permissivity for ampli®cation can be generated by gene products of several DNA tumor viruses whereby their interaction with the tumorsuppressor protein p53 is important. p53 is the major protein involved in check point control of DNA damage. Polyomavirus large T antigen is also involved in immortalization and transformation of cells but it does not interact with p53. We, therefore, examined whether this protein could still make the non-permissive cell line REF52 permissive for gene ampli®cation. To this end REF52 cell lines were constructed which conditionally expressed the wild type polyomavirus large T antigen or a mutant form unable to bind the retinoblastoma protein. Using the inhibitor of de novo pyrimidine biosynthesis, phosphonoacetyl-L-aspartate (PALA), as selective agent we found that PALA resistant cells arise with a frequency of about 5610 75 and that the interaction of polyomavirus large T protein with the retinoblastoma protein or another related pocket protein is important for this to occur. PALA resistant cells have an increased number of chromosomes and dicentric chromosomes which are considered as starting point for DNA structures characteristic for ampli®ed DNA. Such structures were indeed found with the help of uorescence in situ hybridization. PALA resistant cells appear normal with respect to p53. Our data indicate that PALA induces a G 1 block which can be partially overcome by polyomavirus large T protein by its interaction with E2F-pocket protein complexes providing further evidence that these complexes are downstream targets of p53.

show abstract

“…Inactivation of wild-type p53 represents a key step during tumor progression, which has been causally linked to its function in maintaining genomic integrity (Livingstone et al, 1992;Yin et al, 1992;Carder et al, 1993;Harvey et al, 1993). In response to DNA damaging treatments latent p53 becomes activated (Siegel et al, 1995;Lutzker and Levine, 1996) to induce cell cycle arrest or apoptosis in order to prevent the proliferation of genetically damaged cells (for review see Jacks and Weinberg, 1996).…”

Section: Introductionmentioning

confidence: 99%

Dissociation of the recombination control and the sequence-specific transactivation function of P53

et al. 1999

View full text Add to dashboard Cite

Recently, we described a new biological function of p53 in inhibiting recombination processes when encountering mismatches in heteroduplexes (DudenhoÈ er et al., 1998). Here, we characterized protein domains of p53 participating in this process by in vitro analysis of mutated p53 proteins, and by applying our SV40-based assay system on monkey cells, which express di erent p53 variants. We present evidence that both binding of arti®cial recombination intermediates and p53-dependent recombination control require an intact p53 core and the oligomerization domain, strongly suggesting that the recognition of DNA undergoing recombination represents an essential step of this genomic surveillance mechanism. Further analyses indicated a role of the C-terminus in negatively regulating recombination control, an e ect which can be neutralized by concurrent mismatch recognition. p53 lacking the oligomerization domain totally lost its ability to suppress homologous recombination. The cancer-related mutant p53(273H) was also signi®cantly defective in this function, although we observed only twofold reductions in the corresponding transactivation activities on p53-response elements in episomal constructs. HDM2, an inhibitor of p53's transcriptional and growth regulatory activities, interfered with the inhibition of DNA exchange processes by p53 only weakly. Thus, functions of p53 in recombination control can be structurally dissociated from p53-dependent transcriptional transactivation.

show abstract

Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles

Cited by 1,040 publications

References 53 publications

A functional analysis of p53 during early development of xenopus laevis

A functional analysis of p53 during early development of xenopus laevis

Polyomavirus large T antigen-dependent DNA amplification

Dissociation of the recombination control and the sequence-specific transactivation function of P53

Contact Info

Product

Resources

About