Somatic Mutations of the MTS (Multiple Tumor Suppressor) 1/CDK41 (Cyclin-Dependent Kinase-4 Inhibitor) Gene in Human Primary Non-small Cell Lung Carcinomas

Hayashi, Nariyuki; Sugimoto, Yoshihisa; Tsuchiya, Eiju; Ogawa, Minoru; Nakamura, Y.

doi:10.1006/bbrc.1994.2090

Cited by 117 publications

(52 citation statements)

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“…Substituting V95 with alanine signi®cantly reduced the e ectiveness of the peptide (FaÊ hraeus et al, 1996) but this does not appear to be the case in the full length protein. Thus, although this substitution was recorded in a survey of non-small cell lung cancers (Hayashi et al, 1994), our data suggest that V95A is either a polymorphism or a sequencing error.…”

Section: Relative Merits Of Functional Assays For P16 Ink4acontrasting

confidence: 56%

“…Five di erent mutations have been recorded at D84, changing the encoded amino acid to H, N, Y, E or V (Hayashi et al, 1994;Mori et al, 1994;Zhang et al, 1994;Gonzalez-Zulueta et al, 1995;Komiya et al, 1995;Liu et al, 1995;Tamimi et al, 1996;Marchetti et al, 1997;Olshan et al, 1997) and previous functional assays on D84 variants have given inconsistent results (Koh et al, 1995;Enders et al, 1996;Tevelev et al, 1996;Yarbrough et al, 1996). However, all three of the D84 variants tested here proved to be functionally impaired (Table 1).…”

Section: Relative Merits Of Functional Assays For P16 Ink4amentioning

confidence: 62%

“…An obvious source of concern was that the interaction Yoshida et al, 1995;Sou®r et al, 1998) (Liu et al, 1995) (Zhang et al, 1994;Liu et al, 1995;Pollock et al, 1995;Platz et al, 1997) (Walker et al, 1995;FitzGerald et al, 1996;Flores et al, 1997;Harland et al, 1997;Sun et al, 1997;Sou®r et al, 1998) (Hussussian et al, 1994) (Hayashi et al, 1994;Komiya et al, 1995;Liu et al, 1995;Tamimiet al, 1996) (Hayashi et al, 1994;Mori et al, 1994;Zhang et al, 1994) (Hayashi et al, 1994) (Ohta et al, 1994;Pollock et al, 1995) (Hayashi et al, 1994) (Hussussian et al, 1994;Kamb et al, 1994;Whelan et al, 1995;Sou®r et al, 1998) (Borg et al, 1996;Platz et al, 1997) (Harland et al, 1997) (Yoshida et al, 1995) (Okamoto et al, 1994;Gonzalez-Zulueta et al, 1995;Suzuki et al, 1995) (Hayashi et al, 1994;Marchetti et al, 1997) The variant forms of p16 INK4a are identi®ed by the residue number¯anked by the wild-type and variant amino acids in single letter code. Thus, L16P refers to the substitution of proline for leucine at position 16.…”

Section: Ectopic Expression Of P16 Ink4a Variants In Tig-er Cellsmentioning

confidence: 99%

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Functional evaluation of tumour-specific variants of p16INK4a/CDKN2A: correlation with protein structure information

et al. 1999

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Section: Relative Merits Of Functional Assays For P16 Ink4acontrasting

confidence: 56%

Section: Relative Merits Of Functional Assays For P16 Ink4amentioning

confidence: 62%

Section: Ectopic Expression Of P16 Ink4a Variants In Tig-er Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Functional evaluation of tumour-specific variants of p16INK4a/CDKN2A: correlation with protein structure information

et al. 1999

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“…In contrast, homozygous deletions and/or mutations occur more often in mesotheliomas (Cheng et al, 1994), melanomas (Hussussian et al, 1994), non-small-cell lung carcinomas (Hayashi et al, 1994), glioblastomas (Schmidt et al, 1994) and several other tumours (Mori et al, 1994;Caldas et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Sporadic CDKN2 (MTS1/p16ink4) gene alterations in human ovarian tumours

Schuyer

Staveren²,

Klijn³

et al. 1996

Br J Cancer

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Cyclins, cyclin-dependent kinases (CDKs) and cyclindependent kinase inhibitors (CKIs) play a key role in cell cycle control. To achieve an orderly progression through the cell cycle, different cyclin -CDK complexes need to be activated and deactivated at appropriate times. Cyclin D-CDK4 is one of the complexes that promotes cell passage through the G1 phase of the cell cycle. It increases the phosphorylation state of the retinoblastoma protein which then releases transcription factors (e.g. E2F) essential for progression into the S-phase (reviewed by Sherr, 1993;Hartwell and Kastan, 1994;Hunter and pines, 1994 al., 1994).Another negative regulator of cyclin D-CDK4/6 activity is the p16 protein, encoded by the CDKN2 (MTSIpl6in'k4/ CDK4I) gene (Serrano et al., 1993;Nobori et al., 1994 (1979) classification the primary and metastatic carcinomas were subtyped into serous (n = 14 primary, n = 5 metastatic), mucinous (n = 4), endometroid (n = 7), clear cell (n = 2), mixed (n = 3), poorly differentiated (n = 1) and unknown (n = 1). To estimate the percentage of tumour cells, frozen sections were made from a representative part of each tumour and stained with haematoxylin and eosin. The

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“…Methylation of the 5' CpG island associated with transcriptional silencing has been investigated in only one study of primary lung tumors where its incidence was 26% . p16 INK4A mutations are less common (0 ± 8%) Cairns et al, 1994;Rusin et al, 1996;Okamoto et al, 1995) except for one study reporting 30% of intragenic mutations (Hayashi et al, 1994). To date, the real prevalence of these three known mechanisms (i.e.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of p16INK4A inactivation in non small-cell lung cancers

Gazzéri¹,

Gouyer²,

et al. 1998

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The cyclin-dependent kinase inhibitor p16 (p16 INK4A / CDKN2/MTS1) is a potent inhibitor of the cyclin Ddependent phosphorylation of the retinoblastoma gene (Rb) product, the inactivation of which induces loss of Rb-dependent G1 arrest through inappropriate phosphorylation of the Rb protein. To analyse the role of p16 INK4A as a tumor suppressor in the genesis of non small cell lung cancers (NSCLC) and correlate loss of p16 INK4A protein expression to genetic or epigenetic mechanisms, we have performed a comprehensive study of p16 status in a series of 43 NSCLC. To this end, we have investigated p16 INK4A protein expression with immunohistochemistry, deletions of the gene by FISH, and determined the methylation status of exon 1a using a PCR-based methylation assay. Finally, possible mutations were studied by SSCP and subsequent sequencing. Twenty one of the 43 (49%) NSCLC studied exhibited an absence of p16 INK4A nuclear staining. Of these, three (14%) had frameshift or missense mutations, seven (33%) displayed methylation of exon1a and 10 (48%) displayed homozygous deletions. In total, 95% of the tumors with p16 INK4A negative staining carried one of these three alternative genetic or epigenetic alterations. Furthermore, a high degree of chromosome 9 polysomy was found (58%) in those tumors with p16 INK4A inactivation. Taken together these results suggest that deregulation of the p16 gene locus is a frequently occurring event in NSCLC through distinct mechanisms including rare point mutations, promotor methylation and frequent homozygous deletions. Furthermore, our data show that immunohistochemistry is a rapid and an accurate technique for screening of p16 INK4A gene inactivation events that result in loss of protein expression.

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Somatic Mutations of the MTS (Multiple Tumor Suppressor) 1/CDK41 (Cyclin-Dependent Kinase-4 Inhibitor) Gene in Human Primary Non-small Cell Lung Carcinomas

Cited by 117 publications

References 0 publications

Functional evaluation of tumour-specific variants of p16INK4a/CDKN2A: correlation with protein structure information

Functional evaluation of tumour-specific variants of p16INK4a/CDKN2A: correlation with protein structure information

Sporadic CDKN2 (MTS1/p16ink4) gene alterations in human ovarian tumours

Mechanisms of p16INK4A inactivation in non small-cell lung cancers

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