Characterization of p53 oligomerization domain mutations isolated from Li–Fraumeni and Li–Fraumeni like family members

Lomax, Martine E.; Barnes, Diana M.; Hupp, Ted R.; Picksley, Steven M.; Camplejohn, R. S.

doi:10.1038/sj.onc.1201974

Cited by 93 publications

(109 citation statements)

References 19 publications

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“…It should be noted, however, that in vivo the ability to form homo-or hetero-oligomers also may be modulated by the present of DNA binding sites and by the presence of several proteins that recently have been shown to specifically interact with the tetramerization domain. Mutant p53 with Arg337 changed to Cys, a change which is associated with Li-Fraumeni-like syndrome, also forms hetero-tetramers with wild-type p53; however, the hetero-tetramer retains some functional activity including DNA binding and an ability to activate transcription of some genes (49,59,60). However, the thermal stability of the R337C mutant is much lower than that of wild-type p53, and at physiological temperatures, less than half of this mutant is tetrameric.…”

Section: Discussionmentioning

confidence: 99%

Unfolding, Aggregation, and Amyloid Formation by the Tetramerization Domain from Mutant p53 Associated with Lung Cancer

et al. 2006

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The p53 tumor suppressor is a tetrameric transcriptional enhancer, and its activity is compromised by mutations that cause amino acid substitutions in its tetramerization domain. Here we analyze the biochemical and biophysical properties of peptides corresponding to amino acids 319 to 358 of wildtype human p53, which includes the tetramerization domain, and that of a cancer-derived mutant with valine substituted for glycine 334. Unlike the wild-type peptide, the G334V peptide forms amyloid fibrils by a two step process under physiological conditions of temperature and pH. Nevertheless, the G334V peptide is capable of forming hetero-oligomers with a wild-type peptide. Computational modeling of the G334V peptide structure suggests that substitution of valine for glycine 334 causes a local distortion that contributes to a β-dominated structural transition leading to amyloid formation. Since the distortion is mostly on the surface, the mutant peptide is still able to form a pseudo-native tetramer complex at higher concentrations and/or lower temperatures. Our † KS was supported in

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Section: Discussionmentioning

confidence: 99%

Unfolding, Aggregation, and Amyloid Formation by the Tetramerization Domain from Mutant p53 Associated with Lung Cancer

et al. 2006

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“…This appears to be due to the binding of the peptides to the p53 NES such that when these p53/peptide heterocomplexes enter the nucleus, they may be incapable of nuclear export because the binding surface recognized by the export receptor is hidden by the peptide. Tetrameric p53 is most e ective at binding and transactivating p53 response elements, and mutations which prevent tetramerization compromise DNA binding, diminish transactivation, and lead to tumorigenesis (Friedman et al, 1993;Hainaut et al, 1994;Halazonetis and Kandil, 1993;Hupp and Lane, 1994;Ishioka et al, 1995;Lomax et al, 1998;McLure and Lee, 1998;Pietenpol et al, 1994;Tarunina et al, 1996;Varley et al, 1996). Therefore, stress-induced modi®cations which allow p53 tetramerization to occur may concurrently contribute to both the formation of DNA-binding tetramers and to their retention in the nucleus.…”

Section: Linking P53 Activation With Its Subcellular Localizationmentioning

confidence: 99%

p53 regulation by post-translational modification and nuclear retention in response to diverse stresses

et al. 1999

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p53 activation by diverse stresses involves post-translational modi®cations that alter its structure and result in its nuclear accumulation. We will discuss several unresolved topics regarding p53 regulation which are currently under investigation. DNA damage is perhaps the best-studied stress which activates p53, and recent data implicate phosphorylation at N-terminal serine residues as critical in this process. We discuss recent data regarding the potential kinases which modify p53 and the possible role of the resulting phosphorylation events. By contrast, much less is understood about agents which disrupt the mitotic spindle. The cell cycle phase, induction signal, and biochemical mechanism of the reversible arrest induced by microtubule disruption are currently under investigation. Finally, a key event in response to any genotoxic stress is the accumulation of p53 in the nucleus. The factors which determine the steady state level of p53 are starting to be elucidated, but the mechanisms responsible for nuclear accumulation and nuclear export remain controversial. We discuss new studies revealing a mechanism for nuclear retention of p53, and the potential contributions of MDM2 to this process.

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“…In a yeast functional assay for transactivation that usually yields large white colonies for active p53 and small red colonies for inactive p53, R337C produced medium-sized pink colonies (Lomax et al, 1997). Likewise in assays for the ability of p53 to trigger apoptosis (Lomax et al, 1997), activate a reporter gene or suppress growth (Lomax et al, 1998) R337C had an activity intermediate between WT and completely inactive p53. Thus, in all in vivo assays R337C has an intermediate level of activity.…”

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confidence: 99%

“…An additional consequence of defective oligomerization may be an alteration in the interactions of p53 with other cellular proteins. For example, Lomax et al (1998) have shown that both L344P and R337C have reduced ability to bind to MDM2 which forms a negative feedback regulatory loop with p53. Other proteins such as tms1 (Wagner et al, 1995) and p34 cdc2 (Wagner et al, 1998) interact with residues in the tet domain spanning the R337C mutation site.…”

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confidence: 99%

Characterization of the oligomerization defects of two p53 mutants found in families with Li–Fraumeni and Li–Fraumeni-like syndrome

et al. 1998

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Recently two germline mutations in the oligomerization domain of p53 have been identi®ed in patients with Li ± Fraumeni and Li ± Fraumeni-like Syndromes. We have used biophysical and biochemical methods to characterize these two mutants in order to better understand their functional defects and the role of the p53 oligomerization domain (residues 325 ± 355) in oncogenesis. We ®nd that residues 310 ± 360 of the L344P mutant are monomeric, apparently unfolded and cannot interact with wild-type (WT) p53. The full length L344P protein is unable to bind sequence speci®cally to DNA and is therefore an inactive, but not a dominant negative mutant. R337C, on the other hand, can form dimers and tetramers, can hetero-oligomerize with WTp53 and can bind to a p53 consensus element. However, the thermal stability of R337C is much lower than that of WTp53 and at physiological temperatures more than half of this mutant is less than tetrameric. Thus, the R337C mutant retains some functional activity yet leads to a predisposition to cancer, suggesting that even partial inactivation of p53 oligomerization is su cient for accelerated tumour progression.

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Characterization of p53 oligomerization domain mutations isolated from Li–Fraumeni and Li–Fraumeni like family members

Cited by 93 publications

References 19 publications

Unfolding, Aggregation, and Amyloid Formation by the Tetramerization Domain from Mutant p53 Associated with Lung Cancer

Unfolding, Aggregation, and Amyloid Formation by the Tetramerization Domain from Mutant p53 Associated with Lung Cancer

p53 regulation by post-translational modification and nuclear retention in response to diverse stresses

Characterization of the oligomerization defects of two p53 mutants found in families with Li–Fraumeni and Li–Fraumeni-like syndrome

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