p53 and MDM2 Expression in Oral Squamous Cell Carcinoma

Matsumura, Tomohiro; Yoshihama, Yasuto; Kimura, Takuji; Shintani, Satoru; Alcalde, Rafael

doi:10.1159/000227578

Cited by 50 publications

(43 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…MDM2 is another p53 inhibitor present in high levels in HNSC [15][16]. In this study, we observed that many tumors expressed high levels of both, MDM2 and MDM4.…”

Section: Discussionsupporting

confidence: 48%

“…These data suggest that increased levels of MDM2 may substitute for mutations in p53, which represents an alternative mechanism by which tumor cells escape from the tumor suppressive activities of p53. In HNSC, overexpression of MDM2 has been observed [15][16], but a clear correlation between the levels of MDM2 protein and p53 status has not been established [17].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

High levels of the p53 inhibitor MDM4 in head and neck squamous carcinomas

et al. 2007

View full text Add to dashboard Cite

The p53 tumor suppressor is mutated in the majority of human tumors. MDM2, a well-known inhibitor of p53, is overexpressed in a large number of tumors suggesting that increased levels of MDM2 also contribute to tumorigenesis. A novel p53 inhibitor, MDM4, was more recently identified. The role of MDM4 in cancer development is not well understood. We set out to examine the levels of MDM4 by immunohistochemistry in Head and Neck Squamous Carcinomas (HNSC) to ask whether high MDM4 levels could contribute to its development and progression. In addition, MDM2 and p53 levels were examined to identify overlapping expression patterns. MDM4 is present at high levels in 50% of HNSC. Additionally, overexpression of MDM2 was detected in 80% of tumors, many of which were also positive for MDM4. A subset of tumors displayed high levels of all three proteins. Sequencing of the p53 gene revealed that tumors with positive immunoreactivity for MDM2 or MDM4, some of which also had high levels of p53, did not carry mutations in this gene. Thus, the detection of p53 by immunohistochemistry was not synonymous with the presence of p53 mutations. Expression of both MDM2 and MDM4 in tumors without p53 mutations strongly suggests that MDM2 and MDM4 inhibit the activity of this tumor suppressor in HNSC.

show abstract

“…MDM2 is another p53 inhibitor present in high levels in HNSC [15][16]. In this study, we observed that many tumors expressed high levels of both, MDM2 and MDM4.…”

Section: Discussionsupporting

confidence: 48%

Section: Introductionmentioning

confidence: 99%

High levels of the p53 inhibitor MDM4 in head and neck squamous carcinomas

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Incubation with the primary antibodies (monoclonal MDM2 antibody, IF-2, Oncogene Science, USA, and monoclonal p53 antibody, DO-7, Novocastra Laboratories, UK), British Journal of Cancer (1997) 75(9), [1302][1303][1304][1305][1306][1307][1308] . Cancer Research Campaign 1997 the enzyme colour reaction, haematoxylin counterstaining and mounting were carried out as described elsewhere (Foulkes et al, 1995;Marchetti et al, 1995a and b;McCann et al, 1995;Ofner et al, 1995;Matsumura et al, 1996). Immunostaining results were assessed, taking into account the cancer cells whose nuclei showed positive immunoreactivity for MDM2 ( Figure 1) or p53 protein.…”

Section: Immunohistochemical Analysismentioning

confidence: 99%

“…In immunohistochemical studies using monoclonal anti-MDM2 protein antibody, the incidence of MDM2 immunohistochemical (over)expression in human cancers has been reported to be 30% in bladder cancers (Lianes et al, 1994), 20% in colorectal cancers (Ofner et al, 1995), 3% in ovarian cancers (Foulkes et al, 1995), 40% in oral carcinoma (Matsumura et al, 1996) and 22-41% in breast cancers (Marchetti et al, 1995b;McCann et al, 1995). In NSCLC, whereas Marchetti et al (1995a) reported that MDM2 oncogene product expression was detected immunohistochemically only in three (6%) patients with gene amplification, it was detected in the present study in 24% of patients, independently of MDM2 gene amplification status.…”

Section: Post-operative Prognosismentioning

confidence: 99%

MDM2 gene amplification and expression in non-small-cell lung cancer: immunohistochemical expression of its protein is a favourable prognostic marker in patients without p53 protein accumulation

Higashiyama

Doi²,

Kodama³

et al. 1997

Br J Cancer

125

View full text Add to dashboard Cite

Summary MDM2 is an oncoprotein that inhibits p53 tumour-suppressor protein. Amplification of the MDM2 gene and overexpression of its protein have been observed in some human malignancies, and these abnormalities have a role in tumorigenesis through inactivation of p53 function. To determine the clinicopathological and prognostic value of MDM2 abnormalities in non-small-cell lung cancer (NSCLC), MDM2 gene amplification and its protein expression status were analysed in surgically resected materials. MDM2 gene amplification was detected in only 2 (7%) of the 30 tested patients. MDM2 protein was found immunohistochemically in a total of 48 (24%) of the 201 patients. MDM2 protein was slightly frequently observed in patients with adenocarcinoma, but its presence or absence was not associated with clinicopathological factors such as T-factor, N-factor, stage, tumour size, differentiation or p53 protein status. Overall, MDM2-positive patients tended to have a better prognosis (P = 0.062). In particular, among immunohistochemically p53-negative patients (n = 110), those with positive MDM2 protein expression showed significantly better prognosis (P = 0.039) and, in a multivariate analysis, MDM2 protein status was a favourable prognostic factor (P = 0.037). In contrast, among p53-positive patients (n = 91), there was no difference in prognosis depending on MDM2 protein status. Thus, in the NSCLC patients studied, MDM2 gene amplification was a minor event, but expression of its protein, which was often observed immunohistochemically, was a favourable prognostic marker, especially among patients without p53 protein accumulation. Further study is needed to determine how MDM2 protein expression results in a better prognosis.Keywords: MDM2 gene; non-small-cell lung cancer; p53; prognosis; immunohistochemistry; amplification; fluorescence-based polymerase chain reaction single-strand conformation polymorphism The MDM2 gene was originally identified and cloned by amplification in a transformed tumorigenic Balb/c 3T3 fibroblast cell line (Cahilly-Snyder et al, 1987;Fakharzadeh et al, 1991;Oliner et al, 1992). Its product, p90, is now considered to form a tight complex with both the wild-type and mutant p53 tumour-suppressor gene protein and to inactivate wild-type p53 function by masking the Nterminal acidic transactivating domain of p53 protein, indicating that abnormalities of the MDM2 gene may be closely associated with tumorigenesis and/or tumour development (Olson et al, 1993; Haines et al, 1994). Indeed, MDM2 gene amplification and overexpression of its product have been described in several types of malignancies in humans. However, the clinicopathological role of these abnormalities has yet to be determined.In lung cancer, p53 abnormalities have been well examined but, to our knowledge, MDM2 abnormalities in this disease have been reported only by Marchetti et al (1995a

show abstract

“…MDM2 is aberrantly expressed in a number of human tumors (12)(13)(14)(15)(16)(17)(18)(19)(20). It forms a negative autoregulatory loop with p53 by binding to its activation domain (21) and inhibiting its functions in transactivation (22)(23)(24), growth arrest (25,26), and apoptosis (26 -28).…”

mentioning

confidence: 99%

The MDM2 C-terminal Region Binds to TAFII250 and Is Required for MDM2 Regulation of the Cyclin A Promoter

Léveillard¹,

Wasylyk

1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

The tumor suppressor p53 regulates the expression of downstream effectors involved in cell cycle arrest, recovery from the arrest, and apoptosis (1-3). The key mediators of these processes are, respectively, the cyclin-dependent kinase (cdk) 1 inhibitor, p21Cip1/Waf1 (4), the proto-oncoprotein MDM2 (mouse double minute 2) (5-10), and the cell death promoting factor Bax (11). MDM2 is aberrantly expressed in a number of human tumors (12)(13)(14)(15)(16)(17)(18)(19)(20). It forms a negative autoregulatory loop with p53 by binding to its activation domain (21) and inhibiting its functions in transactivation (22-24), growth arrest (25, 26), and apoptosis (26 -28). Inhibition of p53 is essential for development, because homozygous inactivation of the MDM2 gene in mice is lethal and is rescued by inactivation of p53 (23, 29). MDM2 regulates a number of factors in addition to p53, including the tumor suppressor pRb (30), its homologue p107 (31), and the transcription factors E2F1/DP1 (32) and MyoD (33).MDM2 has many features of transcription factors, including a nuclear localization signal, a central acidic region similar to a class of activation domains, an adjacent C4 zinc finger that could interact with nucleic acids, and a C-terminal variant C3HC4 Ring finger (34,35). Ring fingers fold into a characteristic motif with two molecules of zinc and mediate interactions with nucleic acids and proteins (36,37). The N-terminal region of MDM2 interacts with p53 (21), E2F1/DP1 (32), and SV40 large T (38). Recently, the acidic region has been shown to interact with the ribosomal protein L5 and the Ring finger has been shown to interact with RNA, suggesting that MDM2 may regulate protein synthesis (39). The effects of MDM2 on p53, pRb, p107, and E2F1/DP1 suggest that one of its major functions is to regulate the cell cycle.Cell cycle progression depends upon cyclin-cdk complexes that are regulated in a complex manner by synthesis and degradation of the cyclins, association with inhibitory subunits, and phosphorylation of activatory and inhibitory sites on the cdks (40 -43). Cyclin A is required for the S phase, passage through G 2 , and mitosis (44 -48). Cyclin A synthesis at the G 1 /S border is tightly regulated at the transcriptional level (49), whereas degradation appears to be restricted to G 2 /M (50). The promoter is repressed during the G 1 phase by factors binding the cell cycle-dependent element (CDE) and cell cycle genes homology region (CHR), and dissociation of these repressors appears to release the activity of positive regulators, leading to activation during S phase (49,(51)(52)(53). There are similar CDE/CHR elements in the cdc2 and CDC25C gene promoters that mediate regulation during the S/G 2 phase (52), whereas related elements control G 1 and G 1 /S phase expression (54). The factors that bind to the CDE and the CHR have not been unambiguously established. E2F/DP1-like factors appear to bind weakly to the CDE (51-53), and there is evidence that the

show abstract

p53 and MDM2 Expression in Oral Squamous Cell Carcinoma

Cited by 50 publications

References 18 publications

High levels of the p53 inhibitor MDM4 in head and neck squamous carcinomas

High levels of the p53 inhibitor MDM4 in head and neck squamous carcinomas

MDM2 gene amplification and expression in non-small-cell lung cancer: immunohistochemical expression of its protein is a favourable prognostic marker in patients without p53 protein accumulation

The MDM2 C-terminal Region Binds to TAFII250 and Is Required for MDM2 Regulation of the Cyclin A Promoter

Contact Info

Product

Resources

About