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Titolo:
Somatic INK4a-ARF locus mutations: A significant mechanism of gene inactivation in squamous cell carcinomas of the head and neck
Autore:
Poi, MJ; Yen, T; Li, J; Song, HJ; Lang, JC; Schuller, DE; Pearl, DK; Casto, BC; Tsai, MD; Weghorst, CM;
Indirizzi:
Ohio State Univ, Coll Med & Publ Hlth, Sch Publ Hlth, Dept Environm Hlth Sci, Columbus, OH 43210 USA Ohio State Univ Columbus OH USA 43210 nm Hlth Sci, Columbus, OH 43210 USA Ohio State Univ, Ohio State Biochem Program, Columbus, OH 43210 USA Ohio State Univ Columbus OH USA 43210 hem Program, Columbus, OH 43210 USA Ohio State Univ, Dept Otolaryngol, Columbus, OH 43210 USA Ohio State UnivColumbus OH USA 43210 Otolaryngol, Columbus, OH 43210 USA Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA Ohio State Univ Columbus OH USA 43210 rehens Canc, Columbus, OH 43210 USA Ohio State Univ, Dept Stat, Columbus, OH 43210 USA Ohio State Univ Columbus OH USA 43210 , Dept Stat, Columbus, OH 43210 USA Ohio State Univ, Dept Biochem, Columbus, OH 43210 USA Ohio State Univ Columbus OH USA 43210 ept Biochem, Columbus, OH 43210 USA
Titolo Testata:
MOLECULAR CARCINOGENESIS
fascicolo: 1, volume: 30, anno: 2001,
pagine: 26 - 36
SICI:
0899-1987(200101)30:1<26:SILMAS>2.0.ZU;2-6
Fonte:
ISI
Lingua:
ENG
Soggetto:
TUMOR-SUPPRESSOR P16(INK4A); CYCLIN-DEPENDENT KINASE-4; P16 GENE; ONCOGENE AMPLIFICATION; HOMOZYGOUS DELETIONS; HIGHER FREQUENCY; ORAL CAVITY; MTS1 GENE; K-RAS; CANCER;
Keywords:
single-stranded conformation polymorphism; point mutations; p16; p14(ARF);
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
57
Recensione:
Indirizzi per estratti:
Indirizzo: Weghorst, CM Ohio State Univ, Coll Med & Publ Hlth, Sch Publ Hlth, Dept Environm Hlth Sci, 1148 CHRI,300 W 10th Ave, Columbus, OH 43210 USA Ohio State Univ 1148 CHRI,300 W 10th Ave Columbus OH USA 43210
Citazione:
M.J. Poi et al., "Somatic INK4a-ARF locus mutations: A significant mechanism of gene inactivation in squamous cell carcinomas of the head and neck", MOL CARCINO, 30(1), 2001, pp. 26-36

Abstract

The INK4a-ARF locus is located on human chromosome 9p21 and is known to encode two functionally distinct tumor-suppressor genes. The p16(INK4a) (p16)tumor-suppressor gene product is a negative regulator of cyclin-dependent kinases 4 and 6, which in turn positively regulate progression of mammaliancells through the cell cycle. The p14(ARF) tumor-suppressor gene product specifically interacts with human double minute 2, leading to the subsequentstabilization of p53 and G(1) arrest. Previous investigations analyzing the p16 gene in squamous cell carcinomas of the head and neck (SCCHNs) have suggested the predominate inactivating events to be homozygous gene deletions and hypermethylation of the p16 promoter. Somatic mutational inactivationof p16 has been reported to be low (0-10%, with a combined incidence of 25of 279, or 9%) and to play only a minor role in the development of SCCHN. The present study examined whether this particular mechanism of INK4a/ARF inactivation, specifically somatic mutation, has been underestimated in SCCHN by determining the mutational status of the p16 and p14(ARF) genes in 100primary SCCHNs with the use of polymerase chain reaction technology and a highly sensitive, nonradioactive modification of single-stranded conformational polymorphism (SSCP) analysis termed "cold" SSCP. Exons 1 alpha, 1 beta, and 2 of INK4a/ARF were amplified using intron-based primers or a combination of intron- and exon-based primers. A total of 27 SCCHNs (27%) exhibited sequence alterations in this locus, 22 (22%) of which were somatic sequence alterations and five (5%) of which were a single polymorphism in codon 148. Of the 22 somatic alterations, 20 (91%) directly or indirectly involvedexon 2, and two (9%) were located within exon Ice. No mutations were foundin exon 1 beta. All 22 somatic mutations would be expected to yield altered p16 proteins, but only 15 of them should affect p24(ARF) proteins. Specific somatic alterations included microdeletions or insertions (nine of 22, 41%), a microrearrangement tone of 22, 5%), and single nucleotide substitutions (12 of 22, 56%). in addition, we analyzed the functional characteristics of seven unique mutant p16 proteins identified in this study by assessingtheir ability to inhibit cyclin-dependent kinase 4 activity. Six of the seven mutant proteins tested exhibited reduced function compared with wild-type p16, ranging from minor decreases of function (twofold to eightfold) in four samples to total loss of function (29- to 38-fold decrease) in two other samples. Overall, somatic mutation of the INK4a/ARF tumor suppressor locus, resulting in functionally deficient p16 and possibly p14(ARF) proteins,seems to be a prevalent event in the development of SCCHN. (C) 2001 Wiley-Liss, Inc.

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Documento generato il 26/01/20 alle ore 01:08:44