`Gain of function' phenotype of tumor-derived mutant p53 requires the oligomerization/nonsequence-specific nucleic acid-binding domain

Transcription regulation by mutant p53

“…Thus it is possible that the nonSSDB activity of the p53 C terminus is also regulating the specificity of mutp53 DNA binding. This idea is supported by the finding that mutp53 DNA binding requires the same domains involved in wtp53-SSDB to non-linear DNA, namely the core domain and the C terminus (Muller et al, 1996;Will et al, 1998), as well as by the finding that these domains were necessary for the transactivation of some promoters by mutp53 (Frazier et al, 1998;Lanyi et al, 1998) and for some of mutp53 oncogenic functions . Further support for this notion is offered by studies showing that post-translational alterations of the C terminus affects mutp53 transcriptional activities (Yap et al, 2004;Di Agostino et al, 2006).…”

“…Several cancer-associated mutp53 isoforms were later shown to confer augmented tumorigenic potential in mice when overexpressed in a variety of cell types, such as p53-null mouse fibroblasts, p53-null human osteosarcoma cells (Dittmer et al, 1993;Lanyi et al, 1998), and T-cell acute lymphoblastic leukemia cells (Hsiao et al, 1994). Analysis of L-12-derived tumors revealed that mutp53 interfered with cell differentiation (Shaulsky et al, 1991), a phenomenon closely associated with tumor progression.…”

“…Many subsequent studies have since then confirmed that a variety of p53 mutants can upregulate the expression of genes involved in various cellular processes implicated in cancerous progression, including growth regulation, metabolism, angiogenesis, drug resistance and genomic instability. For instance, the143A, 175H, 248W, 273H and 281G p53 mutants were shown to elevate the expression of EGFR (Ludes-Meyers et al, 1996), the 143A, 248W and 273H mutants were found to increase IGF-I-R expression (Werner et al, 1996), PCNA was reported to be transactivated by the 281G mutant (Lanyi et al, 1998) and c-myc by mutant 143A (Frazier et al, 1998;Matas et al, 2001), whereas 248W upregulated L37, RPP-1, and S2 ribosomal protein gene expression (Loging and Reisman, 1999), 174Y transactivated c-fos (Preuss et al, 2000), 125A, 248W and 249T transactivated the IGF-II gene (Lee et al, 2000), DUTPase was activated by 248W and 175H (Pugacheva et al, 2002), and 281G upregulated hsMAD1 and NFKB2 (Deb et al, 2002;Iwanaga and Jeang, 2002). In some of those cases, the requirement of an intact N terminus for the transcriptional and oncogenic activities of mutp53 could be demonstrated (Lanyi et al, 1998;Matas et al, 2001;Pugacheva et al, 2002), and in several instances, a partial contribution of the C terminus of mutp53 was also reported (Frazier et al, 1998;Lanyi et al, 1998;Deb et al, 2002).…”

p73 transcriptional activity increases upon cooperation between its spliced forms

“…Recent studies revealed that the p53 281G mutant elicits a gain of function through e ective increase in transcriptional activities mediated by the MDR promoter (Lanyi et al, 1998). Indeed, transfection of this mutant to 10/1 cells revealed markedly increased MDR-driven CAT activity (Figure 3a).…”

“…p73 was co-transfected with the p53 281G mutant (2 mg alone or 1 mg in combination) and (1 mg) (a) MDR or Mdm2-CAT (b) constructs (Lanyi et al, 1998) as indicated in the ®gure. Proteins were prepared and analysed as indicated in the legend to Figure 1, with the exception that the analysis of transcriptional activity was carried out using a kit for monitoring the levels of CAT proteins (CAT-ELISA, Boehringer Mannheim) di erent forms of stress by various members of the p53 family.…”