Gene mutations and increased levels of p53 protein in human squamous cell carcinomas and their cell lines

Burns, Julie E.; Baird, Margaret; Clark, Louise; Burns, Philip A.; Edington, Kirsten G.; Chapman, Christopher G.; Mitchell, Rod T; Robertson, Gerry; Soutar, David S.; Parkinson, E.K.

doi:10.1038/bjc.1993.238

Cited by 118 publications

(68 citation statements)

References 69 publications

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“…The p53 pathway in the SCC lines investigated here has previously been analysed and all of the lines showed evidence for non-functional p53 (Burns et al, 1993;Min et al, 1994;S Timmermann and K MuÈ nger, unpublished). 5-Aza-CdR treatment restored the pRB pathway in SCC cells by re-expressing p16 ink4a protein.…”

Section: Discussionmentioning

confidence: 82%

Re-expression of endogenous p16ink4a in oral squamous cell carcinoma lines by 5-aza-2′-deoxycytidine treatment induces a senescence-like state

1998

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We have previously reported that a set of oral squamous cell carcinoma lines express speci®cally elevated cdk6 activity. One of the cell lines, SCC4, contains a cdk6 ampli®cation and expresses functional p16 ink4a , the other cell lines express undetectable levels of p16 ink4a , despite a lack of coding-region mutations. Two of the cell lines, SCC15 and SCC40 have a hypermethylated p16 ink4A promoter and a third cell line, SCC9, has a mutation in the p16 ink4a promoter. Using the demethylation agent 5-aza-2'-deoxycytidine, we showed that the p16 ink4a protein was re-expressed after a 5-day treatment with this chemical. One cell line, SCC15 expressed high levels of p16 ink4a . In this line, cdk6 activity was decreased after 5-aza-2'deoxycytidine treatment, and the hypophosphorylated, growth suppressive form of the retinoblastoma tumor suppressor protein pRB was detected. Expression of p16 ink4a persisted, even after the drug was removed and the cells expressed senescence-associated b-galactosidase activity. Ectopic expression of p16 ink4a with a recombinant retrovirus in this cell line also induced a similar senescence-like phenotype. Hence, it was possible to restore a functional pRB pathway in an oral squamous cell carcinoma line by inducing re-expression of endogenous p16 ink4a in response to treatment with a demethylating agent.

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Section: Discussionmentioning

confidence: 82%

Re-expression of endogenous p16ink4a in oral squamous cell carcinoma lines by 5-aza-2′-deoxycytidine treatment induces a senescence-like state

1998

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“…Our previous studies have indicated that the immortal phenotype of neoplastic head and neck keratinocytes is showing examples of the LOH described above associated with p53 dysfunction (Burns et al, 1993;Edington et al, 1995), CDKN2A/p16 ink4A dysfunction (Loughran et al, 1994(Loughran et al, , 1996 and a high frequency of allele loss at other genetic loci indicative of multiple suppressor gene loss (Edington et al, 1995, see also Table 2). Therefore, since many other human chromosomal loci have been shown to have antiproliferative e ects reminiscent of replicative senescence when transferred into immortal cells Karlsson et al, 1996;Uejima et al, 1995;Rimessi et al, 1994;Ning et al, 1991;Sandhu et al, 1994Sandhu et al, , 1996Ogata et al, 1993;Koi et al, 1993;Casey et al, 1993;Sasaki et al, 1994;Wang et al, 1992) we decided to investigate the role of these loci in neoplastic human keratinocyte immortalization.…”

Section: Discussionmentioning

confidence: 91%

“…Line BICR 7, is non-senescent, but has a low cloning e ciency and resembles a cell population in crisis (Edington et al, 1995). This line has lost both p53 (Burns et al, 1993) and CDKN2A/p16 ink4A (Loughran et al, 1996) function, in addition to showing LOH at 7q31 (the complementation group D locus). However, the phenotype of BICR 7 is most likely explained by recent results showing it to have very low levels of telomerase (Table 2) whereas all immortal SCC-HN keratinocytes tested had very high levels.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that the process involves one or more recessive inactivating mutations. Two candidates are the p53 and the CDKN2A/p16 ink4A genes which are both inactivated or deleted in immortal but not usually in replicatively senescent neoplastic keratinocytes (Burns et al, 1993Edington et al, 1995;Loughran et al, 1994Loughran et al, , 1996 and we have suggested that the loss of these two suppressor genes in concert is a necessary but insu cient condition to sustain the immortal keratinocyte phenotype in human SCC-HN (Loughran et al, 1994(Loughran et al, , 1996.…”

Section: Introductionmentioning

confidence: 94%

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Evidence for the inactivation of multiple replicative lifespan genes in immortal human squamous cell carcinoma keratinocytes

Loughran

Bond

et al. 1997

Oncogene

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Human keratinocyte immortality is genetically recessive to the normal phenotype of limited replicative lifespan and appears to require the dysfunction of p53 and the cyclin D-Cdk inhibitor p16. In order to test for the inactivation of other candidate replicative lifespan genes in the immortal cells of human tumors, we developed a series of mortal and immortal keratinocyte cultures derived from neoplastic lesions of the head and neck which were amenable to molecular genetic analysis by the loss of heterozygosity (LOH) technique. The results indicate that keratinocyte immortalization in head and neck squamous cell carcinoma (SCC-HN) development involves the inactivation of at least two further pathways to senescence and four in all. Chromosomes 1, 4 and 7 carry genes representing immortality complementation groups C, B and D respectively and immortal keratinocytes showed LOH at either 4q32-q34 between D4S1554 and D4S171 (group B) or 7q31 (group D) but never 1q25 (group C). These results tentatively suggest that the genes responsible for the immortality complementation groups encode proteins on the same pathway to senescence. In addition, all of the immortal keratinocyte lines possessed high levels of telomerase activity and a suppressor of telomerase activity has been mapped to the short arm of chromosome 3p. Five out of eight lines showed LOH at 3p21.2-p21.3, a region which may carry a gene capable of suppressing SCC-HN telomerase. However, alternative mechanisms of telomerase reactivation were also suggested by our results. None of the above genetic alterations were seen in seven senescent neoplastic keratinocyte cultures. Other loci harbouring antiproliferative genes implicated in replicative lifespan showed few or no alterations and any alterations seen were additional to those described above.

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“…In SCCHN deletions have, however, been found in a higher frequency constituting up to 30% of all mutations (Brachman et al, 1992;Burns et al, 1993). The obvious predominance of missense over non-missense mutations is, however, only seen between codons 130 and 286 (Greenblatt et al, 1994).…”

mentioning

confidence: 99%

A non-random deletion in the p53 gene in oral squamous cell carcinoma

Nylander

Schildt²,

Magnusson³

et al. 1996

Br J Cancer

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Summary In a retrospective study of the mutational spectrum of the p53 gene in oral squamous cell carcinoma, 80 primary tumours diagnosed in 1980-90 were included. Using polymerase chain reaction/single strand conformation polymorphism (PCR/SSCP) analysis 47 mutations were found distributed in 39 of the tumours (49%). Unexpectedly, the majority of the mutations (29/47; 62%) were found in exon 8, and at sequencing 17 of them showed a 14 bp deletion in codons 287-292, causing formation of a stop codon and accordingly a truncated protein lacking the C-terminal. The majority of the patients with the 14 bp deletion were women (13/17), and it seemed as though certain potential risk factors for carcinoma of the head and neck were less common in this group.

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Gene mutations and increased levels of p53 protein in human squamous cell carcinomas and their cell lines

Cited by 118 publications

References 69 publications

Re-expression of endogenous p16ink4a in oral squamous cell carcinoma lines by 5-aza-2′-deoxycytidine treatment induces a senescence-like state

Re-expression of endogenous p16ink4a in oral squamous cell carcinoma lines by 5-aza-2′-deoxycytidine treatment induces a senescence-like state

Evidence for the inactivation of multiple replicative lifespan genes in immortal human squamous cell carcinoma keratinocytes

A non-random deletion in the p53 gene in oral squamous cell carcinoma

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