Multiple Murine Double Minute Gene 2 (MDM2) Proteins Are Induced by Ultraviolet Light

Saucedo, Leslie; Myers, Cena D.; Perry, Mary Ellen

doi:10.1074/jbc.274.12.8161

Cited by 40 publications

(65 citation statements)

References 32 publications

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“…We previously demonstrated that, in addition to p90 MDM2 , a smaller MDM2 protein, p76 MDM2 , is expressed in wild-type mouse embryo fibroblasts (MEFs) but not in p53/mdm2-null MEFs (17). In addition, the testis expresses an alternatively spliced mdm2 mRNA that, when expressed in COS-1 cells, produces p76 MDM2 but not p90 MDM2 (17,20). Together, these observations indicate that p76…”

Section: Mdm2mentioning

confidence: 72%

“…Until recently, p90 MDM2 was the only protein known to be a bona fide product of the wild-type mdm2 gene (17). It has long been known that multiple MDM2 proteins are expressed in some tumor cell lines, but it has not been clear whether these proteins are products of normal mRNAs (18,19).…”

Section: Mdm2mentioning

confidence: 99%

“…It has long been known that multiple MDM2 proteins are expressed in some tumor cell lines, but it has not been clear whether these proteins are products of normal mRNAs (18,19). We previously demonstrated that, in addition to p90 MDM2 , a smaller MDM2 protein, p76 MDM2 , is expressed in wild-type mouse embryo fibroblasts (MEFs) but not in p53/mdm2-null MEFs (17). In addition, the testis expresses an alternatively spliced mdm2 mRNA that, when expressed in COS-1 cells, produces p76 MDM2 but not p90 MDM2 (17,20).…”

Section: Mdm2mentioning

confidence: 99%

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p76MDM2 Inhibits the Ability of p90MDM2to Destabilize p53

Perry¹,

Mendrysa²,

Saucedo³

et al. 2000

Journal of Biological Chemistry

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to stimulate the degradation of p53 and leads to an increase in the levels and activity of p53. Seven murine tissues express an alternatively spliced mdm2 mRNA that can encode p76 MDM2 but not p90 MDM2 , as well as the normally spliced mdm2 mRNA that encodes both MDM2 proteins. All seven tissues express both MDM2 proteins. p90 MDM2 is much more abundant than p76 MDM2 in the testis, brain, heart, and kidney. However, in those tissues known to undergo p53-mediated apoptosis in response to ␥-irradiation, the thymus, spleen, and intestine, the levels of the MDM2 proteins are roughly equivalent. Our results indicate that the ratio of the two MDM2 proteins may regulate the response of tissues to DNA damage.

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Section: Mdm2mentioning

confidence: 72%

Section: Mdm2mentioning

confidence: 99%

Section: Mdm2mentioning

confidence: 99%

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p76MDM2 Inhibits the Ability of p90MDM2to Destabilize p53

Perry¹,

Mendrysa²,

Saucedo³

et al. 2000

Journal of Biological Chemistry

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“…MDM2 intracellular levels are controlled by p53, which activates Mdm2 gene transcription from the P2 promoter (Barak et al, 1993;Mendrysa and Perry, 2000), thus establishing a negative feedback control of its activity. Alternative splicing as well as activation of dierent translation start sites may produce MDM2 isoforms exhibiting dierent biologic activities (Olson et al, 1993;Sigalas et al, 1996;Saucedo et al, 1999;. Furthermore, post-translational modi®cations of wild-type protein by caspase cleavage, sumoylation and ubiquitination have been described (Chang et al, 1998;Chen et al, 1997;Pochampally et al, 1998Pochampally et al, , 1999Buschmann et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

MDMX stability is regulated by p53-induced caspase cleavage in NIH3T3 mouse fibroblasts

Gentiletti¹,

Mancini²,

D'Angelo³

et al. 2002

Oncogene

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MDMX is a p53 binding protein, which shares a high degree of homology with MDM2, a negative regulator of the tumor suppressor p53. MDMX has been shown to counteract MDM2-dependent p53 degradation and to stabilize p53 in its inactive form. In this study: we identify two MDMX proteolytic pathways that control its intracellular levels, and show that MDMX posttranslational processing may be regulated by p53. Mouse MDMX is cleaved in vitro and in vivo by caspase activity, between aminoacids 358 and 361, producing a p54 minor form. In addition, MDMX is subjected to proteasome-mediated degradation, which concurs to MDMX proteolysis mainly through degradation of p54. A D361A-MDMX mutant, resistant to caspase cleavage, exhibits prolonged intracellular lifetime in comparison to wild-type protein, indicating that caspase cleavage aects stability of MDMX protein probably by modulating its further degradation. Overexpression of exogenous p53 increases the intracellular levels of p54 product. Similarly, activation of endogenous p53 by adriamycin enhances MDMX cleavage and produces a marked decrease of its intracellular levels, while not aecting the D361A-MDMX mutant. In addition, the D361A-MDMX mutant lacks the ability to inhibit p53 transactivation in respect to wild-type MDMX, suggesting that MDMX caspase cleavage play an important functional role. In conclusion, our results demonstrate that, in analogy to MDM2, MDMX may be subjected to proteolytic modi®cations that regulate its intracellular levels. Moreover, decrease of MDMX protein levels following p53 activation suggests a p53-dependent regulatory feedback of MDMX function.

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“…In the other model, unrepaired lesions interfere with transcription of a gene encoding a short-lived protein involved in p53's degradation (Ljungman et al, 1999). The mdm2 gene ®ts this description since p90 MDM2 is short-lived and its level is regulated through transcription (Juven et al, 1993;Wu et al, 1993;Saucedo et al, 1998Saucedo et al, , 1999. A transcription block that decreased the level of p90 MDM2 could prolong p53's accumulation in TCR-de®cient cells.…”

Section: Introductionmentioning

confidence: 99%

Defects in transcription coupled repair interfere with expression of p90MDM2 in response to ultraviolet light

et al. 2001

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Ultraviolet (UV) irradiation transiently stabilizes p53 through a mechanism that may require a decrease in the activity of the ubiquitin ligase, p90 MDM2 . Conversely, the recovery of low levels of p53 following UV exposure may depend on an increase in p90 MDM2 . The level of p90 MDM2 is increased by UV light following the p53-dependent induction of an internal mdm2 promoter, P2. If this induction of mdm2 were critical for the recovery of low levels of p53 following UV exposure, defects in mdm2's transcription would result in a prolonged increase in p53. Cells defective in transcription coupled repair (TCR) maintain high levels of p53 for a prolonged period following UV exposure. Such cells also have defects in general transcription after UV irradiation. We investigated whether TCR-de®cient cells express diminished levels of mdm2 mRNA and p90 MDM2 following UV exposure. We found that transcription of mdm2 was reduced in TCR-de®cient cells. The uninducible mdm2 promoter, P1, was more sensitive to the inhibitory e ects of UV irradiation than the P2 promoter. The decrease in transcription from the P1 promoter was su cient to reduce the level of p90 MDM2 and correlated with a prolonged increase in p53. Thus, p53-independent transcription of mdm2 appears critical to p53's regulation. Oncogene (2001) 20, 5856 ± 5864.

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Multiple Murine Double Minute Gene 2 (MDM2) Proteins Are Induced by Ultraviolet Light

Cited by 40 publications

References 32 publications

p76MDM2 Inhibits the Ability of p90MDM2to Destabilize p53

p76MDM2 Inhibits the Ability of p90MDM2to Destabilize p53

MDMX stability is regulated by p53-induced caspase cleavage in NIH3T3 mouse fibroblasts

Defects in transcription coupled repair interfere with expression of p90MDM2 in response to ultraviolet light

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