The INK4 family of cell cycle inhibitors in cancer

Roussel, Martine F.

doi:10.1038/sj.onc.1202998

Cited by 278 publications

(217 citation statements)

References 65 publications

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“…A major argument in favour of the above hypothesis comes from comparative analyses of foetal germ cells which share a number of morphological and biochemical features with CIS cells (Jùrgensen et al, 1995;Rajpert-De Meyts et al, 1998;Dieckmann and Skakkebñk, 1999). Given the evidence for high abundance of the p19 INK4d protein during human spermatogenesis (this study), and the structural and biochemical similarities of p19 INK4d with the p16 INK4a tumour suppressor (Ruas and Peters, 1998;Roussel, 1999), we wished to explore the potential role, if any, of p19 INK4d in human testicular germ-cell pathogenesis. As the ®rst step, an immunohistochemical analysis of six prenatal testis specimens (obtained from abortions or upon deaths due to premature birth) from human foetuses between 15 weeks of gestation and birth was performed using either single-antibody staining with DCS-100 against p19 INK4d , or double staining with DCS-100 and an antibody against placental alkaline phosphatase (PIAP).…”

Section: Resultsmentioning

confidence: 87%

“…Genetic analyses of clinical specimens also revealed subsets of primary testicular germ-cell tumours with mutations or promoter methylation of p16 INK4a (Chaubert et al, 1997;Heidenreich et al, 1998), but no aberrations in the p15 INK4b gene (Heidenreich et al, 1998). Finally, loss of p18 INK4c , whose candidacy for a tumour suppressor has so far been supported mainly by studies of mouse models (Franklin et al, 1998;Ruas and Peters, 1998;Roussel, 1999), correlates with progression of human testicular tumours from the carcinoma in situ stage to invasive lesions .…”

Section: Introductionmentioning

confidence: 99%

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Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis

et al. 2000

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p19 INK4d , a member of the INK4 family of cyclindependent kinase inhibitors, negatively regulates the proto-oncogenic cyclin D/CDK4(6) complexes whose ability to phosphorylate the retinoblastoma tumour suppressor (RB) promotes G1/S transition. In contrast to the related p16 INK4a tumour suppressor, expression patterns of 19 INK4d in human tissues and tumours remain unknown. As the RB pathway is commonly targeted in cancer, and mouse models suggest a role for p19 INK4d in spermatogenesis, we examined the abundance and localization of p19 INK4d in the human testis, both during normal development and at various stages of germ-cell tumour pathogenesis. Our data show that the p19 INK4d protein is abundant in spermatocytes of normal human adult testes, whereas virtually no p19 INK4d is detectable in testicular cancer, including the preinvasive carcinoma in situ stage. Together with the lack of p19 INK4d in human foetal germ cells, these results support the concept of foetal origin of the testicular germ-cell tumours, and help better understand the emerging role of the RB pathway in spermatogenesis and tumorigenesis in the human testis. Oncogene (2000) 19, 4146 ± 4150.

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Section: Resultsmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis

et al. 2000

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“…We previously suggested that transcription regulating agents of tumor-suppressor genes, downstream target genes or functionally similar genes of tumor-suppressor genes may be useful for the prevention of tumors, which we therefore termed 'gene-regulating chemoprevention' and 'molecular-targeting prevention' of cancer (10,11 (3), and these four members constitute the INK4 family of proteins. Members of this family negatively regulate the cyclin D-CDK4/6 complexes that promote G1/S transition by phosphorylating the RB tumor-suppressor gene product (3) (Fig.…”

Section: Importance Of P16 Ink4a Gene Inactivation In Human Tumorigenmentioning

confidence: 99%

“…On the other hand, genetic alteration of the p18 INK4c gene is a rare event in human tumors (3). From these findings, it was suggested that p16 INK4a , and not p18 INK4c , plays a role in tumor suppression in humans.…”

Section: Importance Of P16 Ink4a Gene Inactivation In Human Tumorigenmentioning

confidence: 99%

“…The key to the development of an effective preventive approach lies in the identification of genes and biochemical pathways involved in human tumorigenesis. The inactivation of p16 INK4a has been extensively reported for most human malignant tumors (3), and further analysis has proven that p16 INK4a is an important molecule with a tumor suppressive function (3).…”

Section: Introductionmentioning

confidence: 99%

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INK4 Family —A promising target for ‘gene-regulating chemoprevention’ and ‘molecular-targeting prevention’ of cancer

Matsuzaki

Sakai

2005

Environ Health Prev Med

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Inactivation of the p16 INK4a gene is one of the most frequent defects that contribute to oncogenesis in human cancer, since it is a tumor-suppressor gene. Therefore, functional restoration of p16 INK4a is one of the most effective methods for cancer prevention. We proposed the concept of 'gene-regulating chemoprevention' and 'molecular-targeting prevention' of cancer, which assumes that transcriptional regulation by drugs on tumor-suppressor genes or functionally similar genes to the tumor-suppressor genes contributes to the prevention of human malignancies. The p16 INK4a homologs p15 INK4b , p18 INK4c and p19 INK4d have been recently identified, and these four members constitute the INK4 family of proteins. All directly bind to cyclin D-cyclin dependent kinase (CDK) 4/6 and are therefore specific inhibitors of these complexes. We recently showed that histone deacetylase (HDAC) inhibitors, promising chemopreventive and chemotherapeutical agents, induce p15 INK4b and p19 INK4d gene expression and cause growth arrest, suggesting that both genes are important molecular targets for HDAC inhibitors. Furthermore, we found that 12-O-tetradecanoylphorbol-13-acetate (TPA), which is widely used as a tumor promoter and protein kinase C activator, promotes human cancer cell growth through the down-regulation of p18 INK4c gene expression. This suggests that a mouse two-stage carcinogenesis model using TPA might partially represent the most common human carcinogenesis pathway related to RB. Our results suggest that the INK4 family consists of attractive and promising molecular targets for the 'gene-regulating chemoprevention' and 'molecular-targeting prevention' of cancer.

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Transforming growth factor-? signaling in cancer

Rich

Borton

Wang

2001

Microsc. Res. Tech.

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Transforming growth factor (TGF‐β) is a multifunctional polypeptide implicated in the regulation of a variety of cellular processes including growth, differentiation, apoptosis, adhesion, and motility. Abnormal activation or inhibition of these TGF‐β regulated processes is implicated in many diseases, including cancer. Cancers can develop through selective exploitation of defects in TGF‐β signaling that occur at several different levels in the pathway. The TGF‐β signal transduction cascade is initiated when TGF‐β binds to transmembrane receptors. The TGF‐β receptors then phosphorylate and activate Smad proteins, which transduce the signal from the cytoplasm to the nucleus. In the nucleus, Smads can bind directly to DNA and cooperate with other transcription factors to induce transcription of TGF‐β target genes. Mutations in target genes, Smads, or the TGF‐β receptor are associated with certain human cancers. Microsc. Res. Tech. 52:363–373, 2001. © 2001 Wiley‐Liss, Inc.

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The INK4 family of cell cycle inhibitors in cancer

Cited by 278 publications

References 65 publications

Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis

Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis

INK4 Family —A promising target for ‘gene-regulating chemoprevention’ and ‘molecular-targeting prevention’ of cancer

Transforming growth factor-? signaling in cancer

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