Inhibition of p53 transactivation required for transformation by adenovirus early 1B protein

Yew, P.Renee; Berk, Arnold

doi:10.1038/357082a0

Cited by 518 publications

(412 citation statements)

References 27 publications

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“…Finally, we suggest that the loss of binding to Mre11 interferes with the inhibition of MRN function and thus may be detrimental to Ad5 E1B-55K transforming function (discussed below). It should be noted, however, that the Mre11 binding-deficient mutant Ad2 E1B-H354 (Yew et al, 1990;Carson et al, 2003) is not defective for transformation of primary BRK cells (Yew and Berk, 1992). This difference in transforming activity of the E1B-55K mutant is unclear.…”

Section: Discussionmentioning

confidence: 97%

Adenovirus type 5 early region 1B 55-kDa oncoprotein can promote cell transformation by a mechanism independent from blocking p53-activated transcription

Härtl

Zeller²,

Blanchette

et al. 2008

Oncogene

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Inhibition of p53-activated transcription is an integral part of the mechanism by which early region 1B 55K oncoprotein (E1B-55K) from adenovirus type 5 (Ad5) contributes to complete cell transformation in combination with Ad E1A. In addition, more recent data suggest that the mode of action of the Ad protein during transformation may involve additional functions and other protein interactions. In the present study, we performed a comprehensive mutational analysis to assign further transforming functions of Ad5 E1B-55K to distinct domains within the viral polypeptide. Results from these studies show that the functions required for transformation are encoded within several patches of the 55K primary sequence, including several clustered cysteine and histidine residues, some of which match the consensus for zinc fingers. In addition, two amino-acid substitutions (C454S/C456S) created a 55K mutant protein, which had substantially reduced transforming activity. Interestingly, the same mutations neither affected binding to p53 nor inhibition of p53-mediated transactivation. Therefore, an activity necessary for efficient transformation of primary rat cells can be separated from functions required for inhibition of p53-stimulated transcription. Our data indicate that this activity is linked to the ability of the Ad5 protein to bind to components of the Mre11/Rad50/NBS1 DNA doublestrand break repair complex, and/or its ability to assemble multiprotein aggregates in the cytoplasm and nucleus of transformed rat cells. These results introduce a new function for Ad5 E1B-55K and suggest that the viral protein contributes to cell transformation through p53 transcription-dependent and -independent pathways.

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Section: Discussionmentioning

confidence: 97%

Adenovirus type 5 early region 1B 55-kDa oncoprotein can promote cell transformation by a mechanism independent from blocking p53-activated transcription

Härtl

Zeller²,

Blanchette

et al. 2008

Oncogene

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“…Some of the tumors positive for p53 may be accumulating wild-type functional p53, since levels of p53 can be stabilized by interactions with other intracellular proteins such as mdm-2, leading to immunohistochemical expression. [28][29][30] In addition, p53 mutations resulting in a stop codon, frameshift, or nonsense mutations may result in altered or truncated proteins that are not detected by immunohistochemistry. 2 In human cancers, accumulation of p53 has been shown to be a good indicator of poor prognosis.…”

Section: Molecular Marker Expression In Oral Cancer M Shiraki Et Almentioning

confidence: 99%

Combined expression of p53, cyclin D1 and epidermal growth factor receptor improves estimation of prognosis in curatively resected oral cancer

et al. 2005

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p53, cyclin D1 and epidermal growth factor receptor (EGFR) are molecular markers that regulate the cell cycle or cell growth and play important roles in tumor development and progression. In this study, we examined the impact of immunohistochemical expression of these markers on tumor progression in 140 oral cancers. p53, cyclin D1 and EGFR were expressed in 64 cases (46%), 54 cases (39%) and 54 cases (39%), respectively, but there was no inter-relationship between any two of these markers. In the association of these markers with clinicopathological features, EGFR expression alone was significantly associated with poor differentiation (P ¼ 0.0008) and invasive growth pattern (P ¼ 0.0003). Any of these markers, including EGFR, had no significant impact on survival. Coexpression of all these markers, however, was significantly associated with invasive growth pattern (P ¼ 0.0149) and shortened survival (P ¼ 0.0181), and was a significant and independent unfavorable prognostic factor (P ¼ 0.0002), along with tumor size (P ¼ 0.0040), nodal metastasis (P ¼ 0.0137) and growth pattern (P ¼ 0.0017) in a multivariate analysis. Simultaneous coexpression of these markers in oral cancers might prove to be a useful indicator for identification of low-or high-risk patients.

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“…p53 (Kao et al, 1990;Yew and Berk, 1992;Yew et al, 1994). The E1B19K protein is a functional homologue of the proto-oncogene Bcl-2 and prevents apoptosis (Rao et al, 1992;Debbas and White, 1993).…”

Section: Cell Cycle Control By Dna-virusesmentioning

confidence: 99%

ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus

2002

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Accumulated knowledge in the molecular processes of tumour development combined with the availability of genetically modified viruses resemble the basis for new promising cancer therapeutics. The main advantages of employing replicationcompetent viruses are achievement of tumour selective killing and amplification of their oncolytic potential within the tumour mass. In this review, we describe the development of ONYX-015, one of the first and most advanced replication-competent viruses for cancer therapy. We discuss the molecular biology of this therapeutic approach and the interesting results obtained with this virus in clinical trials.

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Inhibition of p53 transactivation required for transformation by adenovirus early 1B protein

Cited by 518 publications

References 27 publications

Adenovirus type 5 early region 1B 55-kDa oncoprotein can promote cell transformation by a mechanism independent from blocking p53-activated transcription

Adenovirus type 5 early region 1B 55-kDa oncoprotein can promote cell transformation by a mechanism independent from blocking p53-activated transcription

Combined expression of p53, cyclin D1 and epidermal growth factor receptor improves estimation of prognosis in curatively resected oral cancer

ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus

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