Reconstitution of p53 expression in a nonproducer Ab-MuLV-transformed cell line by transfection of a functional p53 gene

Wolf, D.; Harris, Nicholas; Rotter, Varda

doi:10.1016/0092-8674(84)90532-4

Cited by 244 publications

(152 citation statements)

References 37 publications

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“…Previous reports have shown that some p53 mutants are capable of conferring increased tumorigenicity (Dittmer et al, 1993) and can induce a highly transformed phenotype as well as growth advantage in cell lines (Wolf et al, 1984;Chen et al, 1990). Since we did not detect abnormal forms of p53, association with hsc70 or recognition by monoclonal antibody PAb240 in ABS cells (data not shown), it is unlikely that a selection for p53 mutations has occurred during transformation by Ad5 E1 and E4orf6 proteins.…”

Section: Discussionmentioning

confidence: 99%

The adenovirus E4orf6 protein contributes to malignant transformation by antagonizing E1A-induced accumulation of the tumor suppressor protein p53

et al. 1999

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The adenovirus type 5 (Ad5) E4orf6 protein promotes focus formation of primary baby rat kidney (BRK) cells in cooperation with Ad5 E1 proteins. This activity is most likely related to the ability of the E4orf6 protein to bind to p53 and modulate its tumor suppressor functions. In this study we report that transformed BRK cells that stably express E4orf6 in addition to E1A and E1B (ABS cells) displayed multiple additional properties commonly associated with a high grade of oncogenic transformation compared to cells expressing only E1A and E1B (AB cells). These properties included morphological alterations, markedly enhanced growth rates and growth to much higher saturation densities. Following injection into nude mice ABS-derived tumors exhibited accelerated growth and, based on histopathological criteria, proofed to be much more malignant compared to tumors generated by AB cells. Interestingly, these highly transformed properties of ABS cells correlated with a dramatic reduction of p53 steady-state levels which inversely correlated with E4orf6 expression. From these results we conclude that expression of the Ad5 E4orf6 protein (i) confers additional transformed in vitro properties to primary rat cells expressing the Ad5 E1 proteins, and (ii) increases the tumorigenic and malignant potential of these cells in vivo. Our data suggest that the Ad5 E4orf6 protein enhances the intrinsic ability of E1-transformed rat cells to grow in a neoplastic state by completely inactivating p53 tumor suppressor function in combination with the E1A and E1B proteins.

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Section: Discussionmentioning

confidence: 99%

The adenovirus E4orf6 protein contributes to malignant transformation by antagonizing E1A-induced accumulation of the tumor suppressor protein p53

et al. 1999

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“…2). The gain of oncogenic activity by mutant p53 was first evidenced by the transfection of mutant p53 into TP53-null cells, conferring these cells with the ability to generate tumors in mice (Wolf et al 1984;Halevy et al 1990;Shaulsky et al 1991). In addition to this GoF effect, certain p53 mutants act via a dominant-negative mechanism in which hetero-oligomerization/aggregation may occur between the mutant and WT p53 proteins .…”

Section: Consequences Of Mutations and Misfolding Of P53 In Cancer Dementioning

confidence: 99%

Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

Costa

Oliveira

Cino

et al. 2016

Cold Spring Harb Perspect Biol

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Prion diseases are disorders that share several characteristics that are typical of many neurodegenerative diseases. Recently, several studies have extended the prion concept to pathological aggregation in malignant tumors involving misfolded p53, a tumor-suppressor protein. The aggregation of p53 and its coaggregation with p53 family members, p63 and p73, have been shown. Certain p53 mutants exert a dominant-negative regulatory effect on wild-type (WT) p53. The basis for this dominant-negative effect is that amyloid-like mutant p53 converts WT p53 into an aggregated species, leading to a gain-of-function (GoF) phenotype and the loss of its tumor-suppressor function. Recently, it was shown that p53 aggregates can be internalized by cells and can coaggregate with endogenous p53, corroborating the prion-like properties of p53 aggregates. The prion-like behavior of oncogenic p53 mutants provides an explanation for its dominant-negative and GoF properties, including the high metastatic potential of cancer cells carrying p53 mutations. The inhibition of p53 aggregation appears to represent a promising target for therapeutic intervention in patients with malignant tumors.

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“…Approximately half the members of Li-Fraumeni families who inherit a mutated p53 allele develop cancer before they reach 30 years of age (Varley et al, 1997a). Some mutant forms of p53 possess a dominant gain-of-function activity which can promote transformation and carcinogenesis even in the presence of a wild-type allele (Dittmer et al, 1993;Eliyahu et al, 1985;Finlay et al, 1989;Liu et al, 2000;Wolf et al, 1984). Clearly, it is of great importance to understand fully how p53 operates.…”

Section: Introductionmentioning

confidence: 99%

RNA polymerase III transcription can be derepressed by oncogenes or mutations that compromise p53 function in tumours and Li-Fraumeni syndrome

et al. 2002

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RNA polymerase (pol) III synthesizes essential small RNAs, including tRNA and 5S rRNA. Wild-type p53 can repress pol III transcription both in vitro and in vivo. Many tumours carry substitutions in p53 which have selective e ects on its functions. We identify tumourderived mutations that compromise the ability of p53 to regulate pol III transcription. Furthermore, substitution R175H, the most common mutation in cancers, converts p53 from a repressor to an activator of pol III. Oncoproteins neutralize p53 in some tumours; we show that human papillomavirus E6 and cellular hdm2 can both release pol III from repression by p53. These data suggest that the restraining in¯uence of p53 on pol III will be lost in many tumours. In addition to these features of sporadic cancers, some individuals inherit mutant forms of p53 and consequently su er from LiFraumeni syndrome, showing genetic predisposition to certain malignancies. We ®nd that pol III transcriptional activity is often highly elevated in primary ®broblasts from Li-Fraumeni patients, especially if the germline p53 mutation is followed by loss of the remaining allele. Our data suggest that p53 status can have a profound e ect upon pol III transcription and hence on the biosynthetic capacity of cells.

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Reconstitution of p53 expression in a nonproducer Ab-MuLV-transformed cell line by transfection of a functional p53 gene

Cited by 244 publications

References 37 publications

The adenovirus E4orf6 protein contributes to malignant transformation by antagonizing E1A-induced accumulation of the tumor suppressor protein p53

The adenovirus E4orf6 protein contributes to malignant transformation by antagonizing E1A-induced accumulation of the tumor suppressor protein p53

Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

RNA polymerase III transcription can be derepressed by oncogenes or mutations that compromise p53 function in tumours and Li-Fraumeni syndrome

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