Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53

Honda, Reiko; Tanaka, Hirofumi; Yasuda, Hideyo

doi:10.1016/s0014-5793(97)01480-4

Cited by 1,758 publications

(1,371 citation statements)

References 25 publications

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“…A key player in this aspect is the E3 ubiquitin ligase Mdm2 (Haupt et al, 1997;Honda et al, 1997;Kubbutat et al, 1997). The interaction between Mdm2 and the N-terminus of p53 obstructs p53-directed transcription and promotes the ubiquitination of lysine residues in the p53 C-terminus and the subsequent targeting of p53 for proteosomal degradation.…”

Section: Introductionmentioning

confidence: 99%

Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation

et al. 2006

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P53 controls the growth and survival of cells by acting in response to a multitude of cellular stresses. It is, however, not yet fully understood how different p53 activation pathways result in either cell cycle arrest or apoptosis. We and others have described an N-terminally truncated p53 protein (p53/47) originating from a second translation initiation site in the p53 messenger RNA (mRNA), which can interact with p53 and impose altered stability and transactivation properties to p53 complexes. Here we show that cap-dependent and cap-independent mechanisms of initiation govern the translation of the p53 mRNA. Changes in synthesis of full-length p53 or p53/47 are regulated through distinct cell stress-induced pathways acting through separate regions of the p53 mRNA. We also show that some cytotoxic drugs require the presence of full-length p53 to induce apoptosis, whereas for others p53/47 is sufficient. This indicates that by harbouring alternative translation initiation sites, the p53 mRNA gives rise to different levels of the p53 isoforms which help to orchestrate the cell biological outcome of p53 activation in response to different types of cell stress. This sheds new light into the way p53 can integrate and differentiate a large multiplicity of changes in the cellular environment.

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Section: Introductionmentioning

confidence: 99%

Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation

et al. 2006

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“…Mdm2 binds the N-terminal transactivation domain of p53, interferes with the recruitment of basal transcription machinery components and inhibits the transcriptional activity of p53. More importantly, Mdm2 binding can also lead to complete proteolytic degradation of p53 through the ubiquitin-proteasome pathway (Honda et al, 1997;Honda and Yasuda, 1999).…”

Section: Introductionmentioning

confidence: 99%

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

et al. 2000

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The tumor suppressor p53 plays a pivotal role in the cellular response to DNA damage as it controls DNA repair, cell cycle arrest and apoptosis. We studied the autoregulation of human p53 gene transcription in colon cancer cell lines. Wild-type p53 has been shown to autoregulate its own transcription either positively or negatively and probably in a cell-type-speci®c manner. Indeed, a p53 binding site has been described in the human and murine p53 promoters, but a direct binding of wild-type p53 protein to this site has never been reported.In this study, we demonstrated a transactivation of human p53 promoter by wild-type p53 in human colon cancer cells. We identi®ed in the human p53 promoter a novel potential p53-responsive element that binds wildtype p53. Moreover, wild-type p53 protein transactivated a reporter plasmid containing a luciferase gene driven by a minimal promoter harboring this p53 binding site. Finally, as the p53 promoter contains an NF-kB binding site, we demonstrated an additive e ect when NF-kB subunits and p53 protein combined to transactivate the human p53 promoter. Oncogene (2000) 19, 4787 ± 4794.

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“…p19 ARF associates with and inhibits Mdm2 (Kamijo et al, 1998;Pomerantz et al, 1998;Stott et al, 1998;Zhang et al, 1998), which acts in a feedback loop to antagonize p53 function by direct binding (Barak et al, 1993;Wu et al, 1993). Mdm2 association with p53 inhibits p53 transcriptional activity (Momand et al, 1992;Oliner et al, 1993), induces p53 ubiquitination (Haupt et al, 1997;Honda et al, 1997;Kubbutat et al, 1997) and accelerates p53 nuclear export and its degradation in cytoplasmic proteosomes (Roth et al, 1998). Consistent with these ®ndings, the E1A-induced apoptosis appears to be dependent on p53-mediated pathways (Debbas and White, 1993;Lowe and Ruley, 1993;Querido et al, 1997;Samuelson and Lowe, 1997).…”

Section: Introductionmentioning

confidence: 99%

Induction of S phase and apoptosis by the human papillomavirus type 16 E7 protein are separable events in immortalized rodent fibroblasts

et al. 2000

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The HPV16 E7 oncoprotein neutralizes several cell cycle checkpoints, favouring the entry of quiescent cells into S phase. This activity is mediated in part by association of E7 with the pocket proteins and consequent activation of E2F transcription factors. In addition, HPV16 E7 protein is able to promote apoptosis. In this study we demonstrate that the ability to induce apoptosis is a common property of E7s belonging to both benign and malignant HPV types. The E7-induced apoptosis is mediated by inactivation of pRb, whilst neutralization of the other two pRB-related proteins, p107 and 130, is not su cient to trigger apoptosis. Moreover, we show that certain point mutations in the conserved region 1 (CR1) of HPV16 E7 abolish the induction of apoptosis without altering the ability to stimulate S phase. Thus, these two E7-mediated cellular events, apoptosis and S phase entry, can be separated in immortalized rodent ®broblasts. Our ®ndings demonstrate that the E7-mediated pRb destabilization is not required for its ability to drive quiescent cells into S phase and to induce apoptosis. Finally, expression of E7 proteins in NIH3T3, which lack a functional p19 ARF , does not lead to p53 accumulation, indicating that the E7 impacts upon additional cellular pathways to promote apoptosis.

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Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53

Cited by 1,758 publications

References 25 publications

Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation

Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

Induction of S phase and apoptosis by the human papillomavirus type 16 E7 protein are separable events in immortalized rodent fibroblasts

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