Inhibition of p53-mediated transactivation and cell cycle arrest by E1A through its p300/CBP-interacting regionSelfcloseTable

Somasundaram, Kumaravel; El‐Deiry, Wafik S.

doi:10.1038/sj.onc.1201002

Cited by 169 publications

(129 citation statements)

References 33 publications

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“…The model proposed in this study suggesting that apoptosis occurs in conditions of p53 induction with limiting levels of p300 may account for one such mechanism. However, we note that other recent studies have suggested that p300 plays a positive role in regulating p53-dependent apoptosis (Avantaggiati et al, 1997;Lill et al, 1997;Somasundaram and El-Deiry, 1997) and, although further experiments are required to clarify these issues, it is possible that the dependence of p53 activity on p53 concentration is a contributory factor.…”

Section: P300 In the Control Of Apoptosismentioning

confidence: 73%

Functional interplay between p53 and E2F through co-activator p300

et al. 1998

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Section: P300 In the Control Of Apoptosismentioning

confidence: 73%

Functional interplay between p53 and E2F through co-activator p300

et al. 1998

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“…46 Disruption of p300 binding to E1a has been shown to restore p53 activity. 47,48 Therefore, in addition to an E1b-19kD deletion, an E1a modification that impairs p300 and p400/TRAPP binding could be useful to optimize the cell killing activity of a p53-expressing vector.…”

Section: Discussionmentioning

confidence: 99%

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

et al. 2006

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Clinical efficacy of adenovirus-mediated cancer gene therapy has been limited thus far. To improve its oncolytic effect, a replication-competent adenoviral vector was previously constructed to express high levels of p53 at a late time point in the viral life cycle. p53 expression from this vector improved tumor cell killing and viral spread in vitro. However, p53 function is antagonized by cellular mdm2 and adenoviral E1b-55kD, both of which are known to bind to and inactivate p53. Therefore, a new vector (Adp53W23S) that expresses a modified p53 transgene, which does not bind to E1b-55kD and mdm2, was constructed. The modified p53 protein was demonstrated to have a substantially prolonged half-life, and its localization was predominantly nuclear. Viral replication was unaffected by expression of the modified p53 and cancer cell killing was improved in vitro. However, in a xenograft model, efficacy was not significantly different from control virus. In conclusion, expression of a degradation-resistant p53 transgene late in the life cycle of a replication-competent adenovirus improves p53 stability and cancer cell killing in vitro. However, other factors, such as the adenoviral E1b-19kD and E1a proteins, which oppose p53 function, and limitations to viral spread need to be addressed to further improve in vivo efficacy.

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“…Binding of p300/CBP by E1A inhibits the transcription of the p21 CIP1/WAF1 induced by DNA damage (Steegenga et al, 1996;Somasundaram and el-Deiry, 1997), transforming growth factor-b (TGF-b) (Datto et al, 1997), keratinocytes and myoblasts terminal differentiation (Missero et al, 1995;Cenciarelli et al, 1999). In the cases above mentioned, the transcription of p21 CIP1/WAF1 depends either on p53 (Vogelstein et al, 2000) or on differentiation-specific factors like MyoD (Cenciarelli et al, 1999), RB family proteins and small DNA virus oncoproteins A Felsani et al and p300/CBP is the transcriptional coactivator both of p53 (Avantaggiati et al, 1997;Lill et al, 1997) and MyoD (Eckner et al, 1996;Yuan et al, 1996).…”

Section: Adenovirus Early-region 1amentioning

confidence: 99%