The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation

Momand, Jamil; Zambetti, Gerard P.; Olson, David C.; George, Donna L.; Levine, Arnold J.

doi:10.1016/0092-8674(92)90644-r

Cited by 2,802 publications

(2,049 citation statements)

References 46 publications

Supporting

Mentioning

1,985

Contrasting

Unclassified

Order By: Relevance

“…The adenovirus E1B-55 kDa protein, the human MDM2 protein, and hepatitis B virus X protein, bind to the amino-terminal region of p53 and inhibit its transactivation function (Yew and Berk, 1992;Oliner et al, 1993;Momand et al, 1992;Levine, 1997). Amino acid residues 22 and 23 play a key role in the binding of p53 to E1B-55 kDa and MDM2 Levine, 1997).…”

Section: Amino-terminal Region Of P53mentioning

confidence: 99%

Twenty years of p53 research: structural and functional aspects of the p53 protein

1999

View full text Add to dashboard Cite

Section: Amino-terminal Region Of P53mentioning

confidence: 99%

Twenty years of p53 research: structural and functional aspects of the p53 protein

1999

View full text Add to dashboard Cite

“…Moreover, p53 protein can be stabilized and therefore detected immunohistochemically by binding to various proteins, such as large T antigen, 70-kDa heat-shock protein (Lane, 1992) and MDM2 protein. The last is a 90-kDa protein that has the ability to form complexes with both wild and mutant types of p53 and acts as a specific p53 antagonist by concealing its activation domain (Momand et al, 1992). An autoregulatory feedback loop seems to exist between MDM2 and p53 in the sense that the MDM2 gene is inducible by wild p53 protein whereas MDM2 protein regulates p53 protein at the level of its activity.…”

Section: Discussionmentioning

confidence: 99%

MDM2 and p53 expression in gliomas: a multivariate survival analysis including proliferation markers and epidermal growth factor receptor

Korkolopoulou

Christodoulou²,

Kouzelis³

et al. 1997

Br J Cancer

View full text Add to dashboard Cite

Summary p53 and the murine double minute 2 (MDM2) oncoprotein expression was evaluated in paraffin-embedded tissue from 61 patients with central nervous system gliomas (53 astrocytomas and eight oligodendrogliomas) and related to proliferation-associated markers [i.e. proliferating cell nuclear antigen (PCNA), Ki-67 and nuclear organizer regions (NORs)] and epidermal growth factor receptor (EGFR). We used the monoclonal antibodies PC-1 0, MIB-1, DO-1, 1 Bi 0 and EGFR 113 and the colloid silver nitrate (AgNOR) technique. MDM2 and p53were co-expressed in 28% of cases. A p53-positive/MDM2-negative phenotype was observed in 15% and a p53-negative/MDM2-positive phenotype in 20% of cases. There was a positive correlation of p53 and MDM2 expression with grade and proliferation indices. Univariate analysis in the group of diffuse astrocytomas showed that older age, high histological grade, high PCNA labelling index (LI) and high AgNOR score were associated with reduced overall survival (P < 0.05). p53 LI, Ki-67 LI, AgNOR score, tumour location and grade influenced diseasefree survival (P < 0.05), whereas the only parameters affecting post-relapse survival were histological grade and Ki-67 LI (P < 0.1). Multivariate analysis revealed that age, radiotherapy, PCNA LI and p53 LI were the independent predictors of overall survival. p53 LI, Ki-67 LI, MDM2 LI, EGFR LI, grade and type of therapy were independent predictors of disease-free survival, and grade was the only independent predictor of post-relapse survival. Our results indicate that p53 LI and MDM2 LI, EGFR expression as well as proliferation markers (PCNA and Ki-67) are useful indicators of overall and disease-free survival in diffuse astrocytoma patients.Keywords: proliferating cell nuclear antigen; Ki-67; MIB-1; AgNORs; p53; MDM2; epidermal growth factor receptor; gliomas Central nervous system (CNS) gliomas range in clinical behaviour and histological appearance from indolent well-differentiated lesions to highly anaplastic, rapidly growing neoplasms. A cardinal property of almost all types of gliomas is a propensity to recur and undergo anaplastic change (Russel and Rubinstein, 1989). A major stimulus to the study of cell proliferation in gliomas has been the widely held belief that quantification of this fundamental process will be of value in the objective categorization of these tumours. However, while cell kinetic information is an important aspect of the biology of gliomas, it has become clear that neoplastic evolution towards glioblastoma is a multistep process that involves deregulation of several genes related to both cellular proliferation and differentiation. The molecular determinants of glioma progression are still under investigation, with considerable attention directed towards the tumour-suppressor gene p53. On the basis of findings from molecular genetic analysis, Bigner and Vogelstein (1990)

show abstract

“…The MDM2 protein binds to a region in the N-terminus of p53 representing the transcription activation domain of p53 Oliner et al, 1992). Overexpression of MDM2 protein inhibits both the transcriptional activation and the repression activities of p53 (Chen et al, 1995;Momand et al, 1992). Thus overexpression of MDM2 protein results in a similar e ect to mutational inactivation of p53.…”

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

View full text Add to dashboard Cite

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.

show abstract

The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation

Cited by 2,802 publications

References 46 publications

Twenty years of p53 research: structural and functional aspects of the p53 protein

Twenty years of p53 research: structural and functional aspects of the p53 protein

MDM2 and p53 expression in gliomas: a multivariate survival analysis including proliferation markers and epidermal growth factor receptor

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

Contact Info

Product

Resources

About