Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line.

Fakharzadeh, Steve; Trusko, Stephen P.; George, Donna L.

doi:10.1002/j.1460-2075.1991.tb07676.x

Cited by 634 publications

(528 citation statements)

References 24 publications

(20 reference statements)

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“…The ampli®ed sequences originate from chromosome 10, region C1-C3. NIH3T3 or Rat2 cells overexpressing only the cloned Mdm2 gene were tumorigenic in nude mice, indicating that Mdm2 by itself possesses transforming activity (Fakharzadeh et al, 1991). Independently, characterization of a 90 kD protein associated with p53 (Hinds et al, 1990;Barak and Oren, 1992) led to the identi®cation of this protein as a product of the Mdm2 gene (Momand et al, 1992).…”

Section: From Double Minute Chromosomes To P53mentioning

confidence: 99%

“…The full length mouse Mdm2 protein is composed of 489 amino acids (aa) (Fakharzadeh et al, 1991). A comparison between the primary sequences of murine, human (491 aa) (Oliner et al, 1992), Xenopus laevis (473 aa) (Marechal et al, 1997) and zebra®sh Mdm2 (445 aa) (HN and JP, unpublished) allows identification of four major conserved regions (Figures 1 and 2).…”

Section: Structure and Function Of Mdm2 Protein: The P53 Binding Domainmentioning

confidence: 99%

“…Region I includes about 90 aa of the N-terminus lacking obvious sequence domains (46% identity), region II is included in a highly acidic region (62% identity), region III contains a potential zinc ®nger (58% identity), region IV contains a ring-®nger (83% identity) (Boddy et al, 1994). A short basic region with a potential nuclear localization signal is also conserved (Fakharzadeh et al, 1991).…”

Section: Structure and Function Of Mdm2 Protein: The P53 Binding Domainmentioning

confidence: 99%

“…Residues F19, W23 and L26 of p53 insert deeply into Figure 2. The nuclear localization signal (nls) sequence is hypothetic (Fakharzadeh et al 1991). See text for further details Figure 2 A comparison between Mdm2 homologs from di erent vertebrate species.…”

Section: Structure and Function Of Mdm2 Protein: The P53 Binding Domainmentioning

confidence: 99%

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Mdm2: keeping p53 under control

1997

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The Mdm2 gene is overexpressed in several human tumors. The oncogenic potential of Mdm2 is partially explained by the inhibition of the activity of the tumor suppressor protein p53. Determination of the threedimensional structure of complexes between Mdm2 and the N-terminal p53 peptide provided a molecular basis for the inhibition of the transcriptional function of p53 by Mdm2. More dramatically, p53 is targeted by Mdm2 for rapid degradation. The Mdm2 gene itself is activated by p53, which gives the opportunity for feed-back control of p53 activity. Keeping p53 under control is most likely the major task of Mdm2 during early development. Recently, evidence was provided for an alternative, p53-independent function of Mdm2.

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Section: From Double Minute Chromosomes To P53mentioning

confidence: 99%

Section: Structure and Function Of Mdm2 Protein: The P53 Binding Domainmentioning

confidence: 99%

Section: Structure and Function Of Mdm2 Protein: The P53 Binding Domainmentioning

confidence: 99%

Section: Structure and Function Of Mdm2 Protein: The P53 Binding Domainmentioning

confidence: 99%

See 2 more Smart Citations

Mdm2: keeping p53 under control

1997

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“…Overexpression of the mdm2 gene in BALB/c 3T3 cells confers tumorigenicity in nude mice (Fakharzadeh et al, 1991). Later also the corresponding human mdm2 gene was identi®ed (Oliner et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

The carboxy terminus of p53 mimics the polylysine effect of protein kinase CK2-catalyzed MDM2 phosphorylation

Guerra¹,

Götz

Wagner

et al. 1997

Oncogene

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The oncogene product MDM2 can be phosphorylated by protein kinase CK2 in vitro 0.5 ± 1 mol of phosphate were incorporated per mol MDM2 protein. The catalytic subunit of protein kinase CK2 (a-subunit) catalyzed the incorporation of twice as much phosphate into the MDM2 protein as it was obtained with the holoenzyme. Polylysine stimulated MDM2 phosphorylation by CK2 holoenzyme threefold in contrast to the a-subunitcatalyzed MDM2 phosphorylation which was reduced by about 66% when polylysine was added. Full length p53, but also a peptide representing a C-terminal fragment of the tumor suppressor gene product p53 (amino acids 264 ± 393 which also harbors the CK2b interaction site at amino acids 287 ± 340) mimicked the polylysine e ect in all respects, ie. stimulation of phosphate incorporation by CK2 holoenzyme and inhibition in the presence of the catalytic CK2 a-subunit. Stimulation by p53 264 ± 393 was on the average close to twofold and inhibition in the case of the a-subunitcatalyzed MDM2 phosphorylation was about 40%. Phosphorylation of MDM2 by CK2 holoenzyme in the presence of the p21 WAF1/CIP1 , known to be a potent inhibitor of cyclin-dependent protein kinases, also led to a signi®cant reduction of phosphate incorporation into MDM2 indicating that p21 WAF1/CIP1 does not exclusively inhibit cell cycle kinases. Furthermore, these data add new insight into the autoregulatory loop which include p21 WAF1/CIP1 , MDM2 protein, CK2 and p53.

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DISTINCT mdm2/p53 EXPRESSION PATTERNS IN LIPOSARCOMA SUBGROUPS: IMPLICATIONS FOR DIFFERENT PATHOGENETIC MECHANISMS

et al. 1997

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Recent findings have indicated that TP53 inactivation in sarcomas may result from mutation and/or deletion of the TP53 gene or, alternatively, from binding to the MDM2 gene products. To investigate further a possible role of the two genes in sarcomas, 24 large and deep‐seated lipomas and 74 liposarcomas of various subtypes were analysed for mdm2 and p53 overexpression by immunocytochemistry. Nineteen cases of the same series were also molecularly analysed for both MDM2 gene amplification and TP53 mutations, and a further ten cases for non‐random chromosomal abnormalities. In the retroperitoneal well‐differentiated–dedifferentiated (WD–DD) group, 15/16 WD and 8/8 DD liposarcomas displayed the mdm2+/p53+ phenotype, consistent with MDM2 gene amplification in the absence of TP53 mutations. In the non‐retroperitoneal WD–DD group, 5/11 WD liposarcomas also retained the mdm2+/p53+ phenotype whereas all DD liposarcomas showed an immunophenotype and, when assessed, a genotype consistent with mutant TP53. Null mdm2 immunophenotype, coupled with evidence of a specific chromosome translocation t(12;16), was constantly observed in both the usual and the cellular subtypes of myxoid liposarcoma, three cases of which also showed TP53 alterations at the genetic or protein level. Neither mdm2 nor p53 overexpression was observed in the lipomas. The results show the existence of three main pathogenetically distinct groups of liposarcoma. The first retroperitoneal WD–DD group, which represents a novel class of tumours within a single histological category of sarcoma, where MDM2‐mediated inactivation of p53 could be related to the pathogenetic mechanism. The second is the non‐retroperitoneal WD–DD group, where the TP53 mutations appear to correlate with the dedifferentiation process. The third is the myxoid group, which is characterized by its own unique cytogenetic profile and never shows any involvement of TP53 or MDM2 genes. As for diagnostic significance, the absence of mdm2 and p53 reactivity in lipomas seems to represent a useful marker for differential diagnosis from lipoma‐like WD liposarcomas. © 1997 by John Wiley & Sons, Ltd.

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Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line.

Cited by 634 publications

References 24 publications

Mdm2: keeping p53 under control

Mdm2: keeping p53 under control

The carboxy terminus of p53 mimics the polylysine effect of protein kinase CK2-catalyzed MDM2 phosphorylation

DISTINCT mdm2/p53 EXPRESSION PATTERNS IN LIPOSARCOMA SUBGROUPS: IMPLICATIONS FOR DIFFERENT PATHOGENETIC MECHANISMS

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