Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity.

Khleif, Samir N.; DeGregori, James; Yee, Carole; Kaye, Frederic J.; Nevins, Joseph R.; Howley, Peter M.

doi:10.1073/pnas.93.9.4350

Cited by 323 publications

(237 citation statements)

References 56 publications

(55 reference statements)

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“…An identical hybridization pattern was observed with an exon 1a-speci®c probe (data not shown). It was particularly notable that INK4a mRNA was detectable in normal pancreas as it has been shown in numerous situations that the level of INK4a mRNA is below the detection limit of the standard Northern blot and is only detectable by RT ± PCR methods in normal cells (Alcorta et al, 1996;Khleif et al, 1996;Valle et al, 1997;Yeager et al, 1995;Zindy et al, 1997), indicating a very high level of INK4a mRNA in the pancreas as compared to other normal tissues. The p12 transcript, while approximately 30% of the intensity of the INK4a transcript, was also detectable.…”

Section: Ink4a and P12 Are Expressed At High Levels In The Pancreasmentioning

confidence: 99%

Tissue-specific alternative splicing in the human INK4a/ARF cell cycle regulatory locus

Robertson

Jones

1999

Oncogene

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The INK4a/ARF locus on human chromosome 9p resides at the nexus of two critical cell cycle regulatory pathways, the p53 pathway and the retinoblastoma (pRb) gene pathway. Through the use of shared coding regions and alternative reading frames two distinct proteins are produced: INK4a is a cyclin-dependent kinase inhibitor whereas ARF binds the MDM2 protooncogene and stabilizes p53. We have examined the expression patterns of the INK4a/ARF locus at the RNA level in normal human and murine tissues to determine if these genes are coordinately regulated. We found that both INK4a and ARF were expressed in most tissues at low levels detectable only by RT ± PCR. The pancreas was an exception in that it expressed no detectable ARF mRNA but expressed high levels of INK4a mRNA. Furthermore, human pancreas expressed an additional previously unrecognized splice variant of INK4a, termed p12, through the use of an alternative splice donor site within intron 1. The p12 transcript produced a 12 kD protein composed of INK4a exon 1a and a novel intronderived C-terminus. This novel protein did not interact with cdk4 but was capable of suppressing growth in a pRb-independent manner. The implications of the capacity of the INK4a/ARF locus to encode a third transcript, and for pancreatic cancer, in which the INK4a/ARF locus is nearly always altered, are considered.

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Section: Ink4a and P12 Are Expressed At High Levels In The Pancreasmentioning

confidence: 99%

Tissue-specific alternative splicing in the human INK4a/ARF cell cycle regulatory locus

Robertson

Jones

1999

Oncogene

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“…Lack of the INK4 proteins may therefore produce inactivation of the retinoblastoma protein by the active cyclin/CDK complexes, inducing progression from G 1 to S. Support for this mechanistic model comes from the observation that cancer cells de®cient in p16 INK4a have wild-type retinoblastoma protein and vice versa (Okamoto et al, 1994;Tam et al, 1994). Recently, Khleif et al (1996) have reported that increase in the level of free E2F-1, produced by a functional loss of pRb and disruption of the pRb-E2F complex, leads to an inhibition of cyclin D1-dependent kinase activity and induces the expression of p16 INK4a , resulting in a regulatory feedback control of CDK activity. The molecular complexity of the p16 INK4a gene has recently been increased by the ®nding of alternative reading frames, giving rise to two partially di erent transcripts, p16 INK4a and p19 ARF , which are both functionally involved in the inhibition of cell cycle progression (Quelle et al, 1995a; see review by Larsen, 1996).…”

Section: Introductionmentioning

confidence: 99%

Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas

et al. 1997

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A wide panel of murine induced T-cell lymphomas have been analysed for p16 INK4a or p15 INK4b alterations. Only one g-radiation-induced lymphoma showed p16 INK4a homozygous deletion and no other intragenic mutations were found in these INK4 genes. However, de novo methylation of the 5' CpG islands of the murine p15 INK4b and p16 INK4a genes was found to be highly frequent. While p16 INK4a hypermethylation was found in 36% of the neutron-radiation-induced lymphomas and 15% of the gradiation-induced lymphomas, de novo methylation of p15 INK4b occurs in 88% and 42% of these tumors respectively, correlating with de®cient expression of the corresponding mRNA and allelic losses in the p15 INK4b and p16 INK4a chromosome location. These data represent, to our knowledge, the ®rst report on the signi®cant involvement of hypermethylation of these INK4 genes in murine primary tumors. Moreover, they show the importance of allelic losses and CpG island methylation of p15 INK4b gene inactivation and support a tumor suppressor role for p15 INK4b in T-cell lymphomas independent of p16 INK4a .

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“…32 Similarly, the viral E7 protein binds to the tumor suppressor protein pRB and favors the release from E2F-like transcription factors from their complex with active, hypophosphorylated pRB. 33,34 As a consequence, the transcription of RB-regulated genes is activated and thereby subsequently promotes the G1/S-phase progression of the cell cycle. 35 E7 thus mimics inactivation of pRB either through mutation or deletion of the gene or through enhanced phosphorylation by overexpression of the cyclin-dependent kinases (CDK)4 and CDK6, oncogenic mechanisms frequently observed in many other types of cancer (reviewed in refs.…”

mentioning

confidence: 99%

“…Such cells proliferate even in the presence of very high levels of p16 INK4a . Since expression of p16 INK4a underlies a negative feedback control through pRB, 34,49 reduced or lost pRB function should result in enhanced p16 INK4a levels in the respective cells. Taken together, these data suggest that inactivation of pRB through HPV E7 results in enhanced expression of p16 INK4a , which might therefore represent a specific and sensitive biomarker for cells with active expression of HPV oncogenes.…”

mentioning

confidence: 99%

Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri

et al. 2001

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Cytological screening for cervical cancer or its precursors using Papanicolaou's smear test (Pap test) has been highly efficient to reduce the morbidity and mortality of cervical cancer. However, evaluation of the Pap test relies on subjective diagnostic parameters and is affected by a high rate of false-positive and false-negative results. More objective diagnostic parameters to identify truly dysplastic or neoplastic cells in cervical smears as well as in cervical biopsy samples would therefore avoid insecurity for many patients and the high screening costs associated with repeated testing. Cervical dysplasia is induced by persistent infections through highrisk types of human papillomaviruses (HPVs). Outgrowth of dysplastic lesions is triggered by increasing expression of two viral oncogenes, E6 and E7, which both interact with various cell cycle-regulating proteins. Among these is the retinoblastoma gene product pRB, which is inactivated by E7. pRB inhibits transcription of the cyclin-dependent kinase inhibitor gene p16 INK4a . Increasing expression of the viral oncogenes in dysplastic cervical cells might thus be reflected by increased expression of p16 INK4a . In line with this hypothesis, we observed marked overexpression of p16 INK4a in all cervical intraepithelial neoplasm (CIN) I lesions (n ‫؍‬ 47) except those associated with low-risk HPV types (n ‫؍‬ 7), all CIN II lesions (n ‫؍‬ 32), all CIN III lesions (n ‫؍‬ 60) and 58 of 60 invasive cervical cancers. In contrast, no detectable expression of p16 INK4a was observed in normal cervical epithelium (n ‫؍‬ 42), inflammatory lesions (n ‫؍‬ 48) and low-grade cervical lesions (CIN I) associated with low-risk HPV types (n ‫؍‬ 7). Dysplastic cells could also be identified in cervical smears using a specific p16 INK4a monoclonal antibody. These data demonstrate that p16 INK4a is a specific biomarker to identify dysplastic cervical epithelia in sections of cervical biopsy samples or cervical smears.

show abstract

Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity.

Cited by 323 publications

References 56 publications

Tissue-specific alternative splicing in the human INK4a/ARF cell cycle regulatory locus

Tissue-specific alternative splicing in the human INK4a/ARF cell cycle regulatory locus

Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas

Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri

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