Mutational status of overexpressed p16 in head and neck cancer: evidence for germline mutation of p16/p14ARF

Lang, James C.; Borchers, Joonatan; Danahey, Daniel G.; Smith, Sonali M.; Stover, Daniel G.; Agrawal, Anshu; Malone, James P.; Schuller, David E.; Weghorst, Christopher M.; Holinga, A. J.; Lingam, K.; Patel, Chrishma; Esham, B.

doi:10.3892/ijo.21.2.401

Cited by 19 publications

(36 citation statements)

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“…The positive correlation of both LOH and hypermethylation with loss of protein expression for CDKN2A and MLH1 genes (Po0.01, Spearman's test) confirmed the thesis that these are the most important mechanisms for silencing the CDKN2A and MLH1 genes (El-Naggar et al, 1997;Deng et al, 1999;Wheeler et al, 1999). Our results, showing impaired Rb pathway (loss of expression of RB1 and/or of CDKN2A) in 55.9% of analysed cases confirmed the hypothesis that RB1 pathway (55.9%) is commonly disrupted in HNSCC development and progression, with CDKN2A (45%), rather than RB1 (11.8%) being the frequent direct target for inactivation (Lang et al, 2002). Despite the fact that in our series downregulation of MLH1 was observed in 27.5% of cases, analysis of microsatellite instability (MSI) by using BAT 25, BAT 26 and BAT 40 markers showed only low-frequency MSI (MSI-L) in three out of 62 analysed cases (published elsewhere) (Sasiadek et al, 2002).…”

Section: Discussionsupporting

confidence: 82%

Impairment of MLH1 and CDKN2A in oncogenesis of laryngeal cancer

et al. 2004

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Our study aimed at elucidating which genetic alterations tend to form a network and could be applied as molecular markers of larynx squamous cell carcinoma (LSCC). A panel of genes involved in tumorigenesis was investigated. To search for the possible mechanisms of gene silencing, loss of heterozygosity (LOH) was analysed followed by testing DNA methylation and protein expression for those genes found with the highest frequency of LOH (CDKN2A (55.4%), MLH1 (46.0%), RB1 (35.7%)). A correlation of both LOH and hypermethylation with the loss of expression for CDKN2A and MLH1 was found. Disrupted Rb pathway (loss of expression of RB1 and/or of CDKN2A) in 55.9% of analysed cases confirmed the hypothesis that RB1 pathway is altered in head and neck squamous cell carcinomas, with CDKN2A (45%), rather than RB1 (11.8%) being more frequently inactivated. In LSCC, LOH tends to occur together in gene pairs or triplets. The pair MLH1/CDKN2A and triplets MLH1/TSG on 8p22/CDKN2A and MLH1/ CDKN2A/RB1 are related to staging and grading. LOH in MLH1 correlates with lower and LOH in CDKN2A with higher grades of LSCC. It can be concluded that MLH1 and CDKN2A play an important role in LSCC development and progression.

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Section: Discussionsupporting

confidence: 82%

Impairment of MLH1 and CDKN2A in oncogenesis of laryngeal cancer

et al. 2004

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“…For instance, TP53 missense mutations have been shown to be associated with increased levels of protein expression [37]. Allelic imbalance of RB1 gene has been shown to be associated with increased mRNA expression [52] and p16 and p14 overexpression in the presence of intragenic deletions or single point mutations [38]. It could be hypothesised that some genes that are heterozygously deleted an overexpressed, may be potential tumour suppressor genes where the second hit is a missense mutation leading to mRNA overexpression possibly due to dysfunctional negative feedback loops.…”

Section: Discussionmentioning

confidence: 99%

“…Out of these transcripts, ESTs, for NAD(P) dependent steroid dehydrogenase-like (NSDHL), eukaryotic translation initiation factor 4E family member 3 (EIF4E3) and Regulatory factor X 1 (RFX1) showed more frequent deletions than gains and/or amplification, suggesting that these genes were overexpressed when one copy was deleted/dysfunctional, a feature often observed in known tumour suppressor genes mutated in cancer (e.g., TP53 whose expression levels are increased in the presence of inactivating gene mutations [36,37], or p16 and p14 overexpression in the presence of intragenic deletions or single point mutations [38]). …”

Section: Identification Of Genes Whose Expression Correlates With Copmentioning

confidence: 99%

A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines

Mackay

Tamber

Fenwick

et al. 2009

Breast Cancer Res Treat

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“…The first-strand cDNA synthesis was performed using PowerScript Reverse Transcriptase (BD Clontech) as follows: a reaction mixture containing 2.0 µL of total RNA (∼2-5 µg), 2.0 µL of 5× PowerScript RT buffer, 1.0 µL of Oligo d(T) [12][13][14][15][16][17][18] (0.5 µg/ µL), and 1.0 µL of Random Hexamers (50 µM) was incubated at 70°C for 7.5 min and then chilled to 4°C for 10 min. Subsequently, 2.0 µL of 5× PowerScript RT buffer, 2 µL of DTT (0.1 M), 1 µL of dNTPs mixture (25 mM each individual dNTP), 2 µL of 5× PowerScript RT, and 3 µL of distilled water were combined into the reaction mixture, and the reaction mixture was incubated at the following conditions: 30°C for 5 min, 37°C for 30 min, 42°C for 50 min, 50°C for 5 min, and 80°C for 10 min.…”

Section: Yeast Two-hybrid Analysis Of Interactions Between Cdk4 and Pmentioning

confidence: 99%

Dissection of CDK4-Binding and Transactivation Activities of p34^SEI^-¹ and Comparison between Functions of p34^SEI^-¹ and p16^INK4A

et al. 2005

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Recent studies showed that p34 SEI-1 , also known as TRIP-Br1 or SEI-1, plays a dual role in the regulation of cell-cycle progression. It exhibits the transactivation activity and regulates a number of genes required for G1/S transition, while it also binds and activates cyclin-dependent kinase 4 (CDK4) independent of the inhibitory activity of p16. The goals of this paper are to further dissect the two roles and to compare the functions between SEI-1 and p16. (i) Yeast one-hybrid-based random mutagenesis was first used to identify a number of SEI-1 residues important for LexA-mediated transactivation, including residues L51, K52, L53, H54, L57, and L69 located within the heptad repeat (residues 30-88), a domain required for LexA-mediated transactivation, and two residues M219 and L228 at the C-terminal segment that contributes to transactivation through modulating the heptad repeat. (ii) The functional significance of these residues was further confirmed by site-directed mutagenesis. It was also shown that the heptad repeat-involving transactivation is distinct from the well-known acidic region-involving transactivation.(iii) Yeast two-hybrid-based binding analysis was made possible with the transactivation-negative SEI-1 mutants, and the results showed that some of such mutants retain full ability to bind and activate CDK4. (iv) Site-specific mutants of CDK4 were used to show that there are notable differences among SEI-1, p16, and cyclin D2 in binding to CDK4. (v) The expression levels of SEI-1 and p16 were compared in 32 tumor specimens of human squamous cell carcinomas of the head and neck. The results indicate that SEI-1 was consistently overexpressed, while p16 was consistently underexpressed. These results provide important information on the molecular mechanism of the functions of SEI-1 and on the comparison between SEI-1 and p16 at both molecular and cellular levels.The newly defined gene product, p34 SEI-1 , also known as TRIP-Br1 1 (hereafter abbreviated as SEI-1), has been shown to exhibit multiple biological functions (1-3): (a) SEI-1 specifically binds to multiple PHD zinc finger-and/or bromodomain-containing transcription factors, such as KRIP-1 and p300/CBP, and activates/represses a number of genes important for signal transduction and cell-cycle progression (1). (b) SEI-1 directly binds to DP1 and stimulates the transcriptional activity of the E2F1/DP1 complex in a manner that is regulated by Rb and E1A proteins, thus triggering genes required for the G1/S transition (1). (c) SEI-1 physically contacts cyclin-dependent kinase 4 (CDK4) through a domain distinct from its PHD-bromodomaininteracting region and stimulates CDK4-mdeiated phosphorylation of Rb (2, 3). In the presence of tumor suppressor p16, a quaternary complex is formed between SEI-1, CDK4, cyclin D2, and p16, and the stimulation of SEI-1 renders the kinase resistant to the inhibitory effect of p16. (d) In a yeast one-hybrid system, SEI-1 turns on the lac Z reporter † This work was supported by a research grant CA69472

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Mutational status of overexpressed p16 in head and neck cancer: evidence for germline mutation of p16/p14ARF

Cited by 19 publications

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Impairment of MLH1 and CDKN2A in oncogenesis of laryngeal cancer

Impairment of MLH1 and CDKN2A in oncogenesis of laryngeal cancer

A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines

Dissection of CDK4-Binding and Transactivation Activities of p34^SEI^-¹ and Comparison between Functions of p34^SEI^-¹ and p16^INK4A

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Mutational status of overexpressed p16 in head and neck cancer: evidence for germline mutation of p16/p14ARF

Cited by 19 publications

References 0 publications

Impairment of MLH1 and CDKN2A in oncogenesis of laryngeal cancer

Impairment of MLH1 and CDKN2A in oncogenesis of laryngeal cancer

A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines

Dissection of CDK4-Binding and Transactivation Activities of p34SEI-1 and Comparison between Functions of p34SEI-1 and p16INK4A

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Dissection of CDK4-Binding and Transactivation Activities of p34^SEI^-¹ and Comparison between Functions of p34^SEI^-¹ and p16^INK4A