The human oncoprotein MDM2 arrests the cell cycle: elimination of its cell-cycle-inhibitory function induces tumorigenesis

Brown, Doris R.; Thomas, Charles A.; Deb, Sumitra

doi:10.1093/emboj/17.9.2513

Cited by 133 publications

(145 citation statements)

References 58 publications

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“…It is possible that the transfection protocol activates to some extent the antiproliferative function of endogenous p53. Intriguingly, and in contrast to our observations, MDM2 over-expression has been shown to inhibit the cell cycle in normal cells and to a lesser extent in di erent tumour cells (Brown et al, 1998), suggesting that the e ects of MDM2 may be cell type speci®c.…”

Section: Discussioncontrasting

confidence: 99%

“…The`KKLKKRNK' sequence (residues 474 ± 471) of the RING ®nger binds to RNA (Elenbaas et al, 1996;Lai et al, 1998), is a cryptic nucleolar localization sequence (Lohrum et al, 2000;Weber et al, 2000) and could be a nuclear localization signal (Brown et al, 1998). To investigate whether the KR motif is important for the cell cycle e ects, the lysines and arginines were mutated to alanines (KR/AA; Figure 5a).…”

Section: Mutations Of Conserved Cysteines In the Mdm2 Ring Finger Dommentioning

confidence: 99%

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The contribution of the RING finger domain of MDM2 to cell cycle progression

Argentini¹,

Barboule²,

Wasylyk³

2000

Oncogene

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The MDM2 oncoprotein binds to p53 and abrogates p53-mediated G1 arrest and apoptosis. We show that MDM2 over-expression accelerates cell cycle progression of RPMI2650 cells by overcoming the negative e ect of endogenous wild type p53 at the G1/S checkpoint. The interaction with p53 and transcription inhibition are necessary but not su cient. The RING ®nger domain of MDM2 is also required for the positive e ect of MDM2 on the cell cycle. Surprisingly, several point mutants in the zinc binding sites of the RING ®nger are fully competent for cell cycle stimulation even though they abolish MDM2-directed degradation of p53 and MDM2 E3-ligase activity. In contrast, alterations in and around the cryptic nucleolar localization sequence (KR motif) inhibit MDM2-mediated cell cycle progression as well as p53 degradation and MDM2 E3 ligase activity. We found that all the RING mutants decrease inhibition of both p53 dependent reporters and endogenous p21 CIP1/WAF1/SDI1 . These results indicate that the RING ®nger of MDM2 has a role in the regulation of the cell cycle that is independent of p53 degradation and endogenous p21 CIP1/WAF1/SDI1 regulation. Oncogene (2000) 19, 3849 ± 3857.

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Section: Discussioncontrasting

confidence: 99%

Section: Mutations Of Conserved Cysteines In the Mdm2 Ring Finger Dommentioning

confidence: 99%

The contribution of the RING finger domain of MDM2 to cell cycle progression

Argentini¹,

Barboule²,

Wasylyk³

2000

Oncogene

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“…Notably, the short deleted segment of the G form involves the first mdm2 cell growth-inhibitory domain (ID). 11 Since the lack of at least 1 of these domains is sufficient to induce tumorigenesis in murine cell lines, 11 it is possible that this alternative p53-interacting MDM2 gene product may have acquired an additional transforming function not related to the blocking of the transcription activity of p53.…”

Section: Discussionmentioning

confidence: 99%

“…From the alignment of various mammalian mdm2 proteins, it has been possible to identify distinct conserved regions with specific functions. 8,9 In particular, more recently 2 functional stretches, one responsible for the continuous shuttling of the mdm2 protein between the cytoplasm and the nucleus 10 and the other with growth-inhibitory functions, 11 were mapped. The mdm2 protein was demonstrated to interact with RNA 12 and to bind many cellular proteins, [13][14][15] among which the most investigated and intriguing is p53.…”

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confidence: 99%

Analysis of the molecular species generated by mdm2 gene amplification in liposarcomas

et al. 2001

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MDM2 gene is overexpressed in several tumors and its product may be processed into different isoforms, some of which have been demonstrated to possess transforming activity. In a panel of liposarcomas characterized by displaying 4 different combinations of mdm2/p53 immunoreactivity, molecular analysis of amplified MDM2 gene revealed a coexistence of mutated full-length MDM2 messenger RNAs, an out-of-frame splicing mRNA and finally aberrant spliced forms. Two of the latter are reported here for the first time. The molecular differences in this heterogeneous mRNA population seem to mirror distinct functional aspects of the altered encoded mdm2 proteins. In fact, besides the deleted transcripts defective in their ability to bind p53 and known to possess a transforming activity, here we describe both mutated full-length forms and deleted transcripts that still maintain the ability to bind p53 but, based on their mdm2؉/p53؉ immunophenotype, probably fail to signal its degradation. These aberrant forms, which are responsible for the accumulation and inactivation of p53, can contribute, together with the p53 independent transforming forms, to liposarcoma transforming pathway. The MDM2 proto-oncogene was originally isolated from a spontaneously transformed derivative Balb/c3T3 murine cell line 3T3 DM, 1,2 containing sequences located on extrachromosomal double minute entities.The human homologue cDNA was isolated, sequenced and mapped on human chromosome 12q13-14 by Oliner et al. 3 This region is often aberrant in human bone and soft tissue sarcomas, glioblastomas and breast carcinomas, a variety of mammalian tumors containing an excess of MDM2 gene product due to enhanced transcriptions and/or augmented translational efficiency. 4 -7 The relative 90 KDa phosphoprotein, constituted by 491 aa, is evolutionarily conserved and displays a nuclear localization. From the alignment of various mammalian mdm2 proteins, it has been possible to identify distinct conserved regions with specific functions. 8,9 In particular, more recently 2 functional stretches, one responsible for the continuous shuttling of the mdm2 protein between the cytoplasm and the nucleus 10 and the other with growth-inhibitory functions, 11 were mapped. The mdm2 protein was demonstrated to interact with RNA 12 and to bind many cellular proteins, 13-15 among which the most investigated and intriguing is p53. In fact, the aminoterminal region of mdm2 protein can interact with the aminoterminal transactivating region of p53 protein 16 and neutralizes the tumor-suppressor activity of the latter, 16 possibly by concealing this domain. 17,18 p53 and mdm2 are involved in an autoregulatory loop. In DNA damaged cells, the overexpressed p53 transactivates MDM2 gene, and the induced mdm2 protein down-regulates wild-type p53 functions by forming stable complexes with p53. Recent studies have demonstrated that the physical interaction between the 2 proteins results in a rapid p53 degradation at least in part by the ubiquitinproteasome pathway. 19,20 This mechanism is...

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“…The transcript composition revealed that important motifs were deleted. For example, transcripts A and B lacked the ID1 and ID2 sequence that code for domains inhibiting cell cycle progression (Brown et al, 1998). It is thus possible that these proteins function as accelerators of cell division.…”

Section: Discussionmentioning

confidence: 99%

Cirrhotic livers reveal genetic changes in the MDM2-P14ARF system of cell cycle regulators

et al. 2002

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The genesis of hepatocellular carcinoma is promoted by changes in the regulatory MDM2-P14ARF system. The incidence of such changes has to date not been analysed in non-tumourous livers showing regenerative proliferation. In the present study, 24 cirrhotic livers of alcohol-, autoimmue disorder-or HCV-caused genesis were screened for MDM2-P14ARF alterations at the level of protein, DNA and mRNA. Using confocal laser scanning microscopy, the absence of MDM2 and P14ARF expression was detected in all samples except three HCV-infected livers (four livers) which contained hepatocytes overexpressing MDM2 (P14ARF) protein. In two of the samples lacking P14ARF expression, laser microdissection and PCR demonstrated deletion of the P14ARF gene. The P14ARF gene amplified from other specimens did not carry mutations. MDM2 splicing variants were present in tissues from alcohol-and autoimmune disorder-induced cirrhoses. Sequencing of full-size mRNA revealed a MDM2 mis-sense mutation in an alcohol-induced cirrhosis. One sample contained regenerative nodules with genetic instability occurring at MDM2 locus D12S83 according to the data of automatic PCR fragment analysis. In summary, this study gives first evidence for different types of MDM2 and P14ARF alterations in cirrhotic livers. We suggest that the changes impair the regulatory MDM2-P14ARF system, thus possibly favouring regenerative proliferation and transformation.

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The human oncoprotein MDM2 arrests the cell cycle: elimination of its cell-cycle-inhibitory function induces tumorigenesis

Cited by 133 publications

References 58 publications

The contribution of the RING finger domain of MDM2 to cell cycle progression

The contribution of the RING finger domain of MDM2 to cell cycle progression

Analysis of the molecular species generated by mdm2 gene amplification in liposarcomas

Cirrhotic livers reveal genetic changes in the MDM2-P14ARF system of cell cycle regulators

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