Absence of R24C Mutation of the CDK4 Gene in Leukemias and Solid Tumors

Mori, Nozomu; Yang, Rong; Kawamata, Norihiko; Miller, Carl W.; Mizoguchi, Hideaki; Koeffler, H. Phillip

doi:10.1007/bf02983783

Cited by 10 publications

(4 citation statements)

References 14 publications

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“…However, the causal role of these alterations in tumor development is difficult to assess [25]. Present study revealed that there was no germline mutation in codon 24 and 22 of CDK4 and these results support the findings of previous studies [20,26,27]. The potentially dominant Arg24Cys mutation of CDK4 was not detected in Indian patients with squamous cell carcinoma of head and neck [8].…”

Section: Discussionsupporting

confidence: 88%

“…A prior study found that mutations that decreased cyclin binding of CDK4 by greater than 80% also decreased kinase activity [19]. Generally, the level of cyclin binding of the various CDK4 mutants correlates well with kinase activity, and the sequences involved in p16 INK4a binding are a subset of those involved in cyclin D1 binding [20]. Figure 3 shows In silico structural model analysis of CDK4 protein using the UCSF Chimera 1.5.3 program revealed that Ser52Thr and Glu67Gln mutations are located in N terminal domain contain αC helix (aa 1–96).…”

Section: Discussionmentioning

confidence: 99%

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Novel germline CDK4 mutations in patients with head and neck cancer

Sabir

Baig

Mahjabeen

et al. 2012

Hered Cancer Clin Pract

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BackgroundCyclin-dependent kinase 4 (CDK4) together with its regulatory subunit cyclin D1, governs cell cycle progression through G1 phase. Cyclin-dependent kinase inhibitors, including p16INK4A in turn regulate CDK4. In particular, deregulation of the p16/CDK4/cyclin D1 complex has been established in a variety of human tumors including gliomas, sarcomas, melanoma, breast and colorectal cancer. However, changes in CDK4 have rarely been observed.MethodIn this study we used a combination of PCR-SSCP and direct sequencing for mutational screening of CDK4. DNA was isolated from peripheral blood leukocyte of patients with squamous cell carcinoma of head and neck, for screening germline mutations in coding regions of CDK4.ResultsVariations observed in exon 2 and 5 were three missense mutations, g5051G > C (Ser52Thr), g5095G > C (Glu67Gln), g5906C > A, g5907C > G (Pro194Ser) and novel frame shift mutations g7321_23delTGA, g7121_7122insG, g7143delG in exon 7 and 3′UTR respectively.ConclusionIn conclusion, two novel mutations were found in N terminal domain which indicates that CDK4 mutation may play a major role in the development and progression of squamous cell carcinoma of head and neck.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Novel germline CDK4 mutations in patients with head and neck cancer

Sabir

Baig

Mahjabeen

et al. 2012

Hered Cancer Clin Pract

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“…For more details see [79]. in many other types of human neoplasms the R24C CDK4 mutation could not be detected [98,99], and so far, no kinase activating mutations have been identified in CDK2 [100,101].…”

Section: Rb/e2f and Melanomamentioning

confidence: 94%

Rb/E2F: A two-edged sword in the melanocytic system

Halaban

2005

Cancer Metastasis Rev

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Rb is a tumor suppressor that represses the expression of E2F regulated genes required for cell cycle progression. It is inactivated in melanomas and other cancer cells by phosphorylation catalyzed by persistent cyclin dependent kinase (CDK) activity. CDK activity is sustained in melanoma cells mostly by the elimination of the CDK inhibitor p16INK4A and by high levels of cyclins whose expression is maintained by stimuli emanating from activated cell surface receptors and/or mutated intracellular intermediates, such as N-Ras and B-Raf. However, Rb also suppresses the expression of apoptosis genes, and its presence protects normal melanocytes from cell death. Its high expression in human melanoma cells and tumors suggests a similar role in malignant cells as well. The differential release and suppression of E2F transcriptional activity is likely to depend on promoter-specific E2F/Rb interaction. Phosphorylated Rb is displaced from cell cycle genes but not from others. In addition, Rb gene repression is dependent on the nature of Rb-E2F interaction and the activity of the Rb-bound proteins recruited to the promoter. Deciphering the differences in Rb/E2F complex formation in normal and malignant melanocytes is likely to shed light on the mechanism by which Rb can exert tumor suppressing and promoting activities in this cellular system. The Rb/E2F pathway provides opportunities for efficient therapy at multiple levels. Novel drugs can reactivate Rb potential to suppress growth cycle promoting genes. In addition, the high E2F transcriptional activity in melanoma cells can be exploited to deliver cytotoxic molecules specifically to tumors, sparing the normal tissues.

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“…However, several laboratories have been unable to identify the same mutations in other types of cancers including solid tumors, leukaemia and tumor-derived cell lines [38][39][40][41].…”

Section: Cdk4mentioning

confidence: 98%

Improving Cancer Therapeutics by Molecular Profiling

Corchero¹,

Fernández-Salguero²

2005

CDM

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The individualized medicine aims to identify the molecular basis of the individual's response to different therapeutic treatments. Individualized medicine is very relevant for human diseases such as cancer and it has become a major task to accomplish more efficient and specific therapeutics. An individualized response to treatment could underline therapeutic success or failure and, even more, could support the rationale for good or bad prognosis. The use of up to date genomic approaches is changing the way we understand modern medicine in terms of drug efficacy, toxicity and diagnosis. Results from genetic polymorphism studies, gene expression profiling and epigenetics illustrate how pharmacogenomic testing will contribute to the goal of individualized medicine. Antineoplastic drugs are designed to block the anomalous activity of specific molecules (therapeutic targets) that regulate cellular processes such as cell cycle. Understanding the relationship between molecular changes in therapeutic targets and enhanced antitumoral response or chemotherapeutic resistance is crucial to establish the clinical relevance of genomic approaches. The goal of this review is to discuss the basic and the clinical significance of genomic research on drug targets and its impact on the early diagnosis and treatment of cancer. We will also assess how these methodologies could contribute to individualized medicine in oncology. A special focus will be put on oncogenes and tumor suppressor genes. Aspects such as drug efficacy, side effects and the diagnostic value of antineoplastic pharmacogenomic research will be also considered.

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Absence of R24C Mutation of the CDK4 Gene in Leukemias and Solid Tumors

Cited by 10 publications

References 14 publications

Novel germline CDK4 mutations in patients with head and neck cancer

Novel germline CDK4 mutations in patients with head and neck cancer

Rb/E2F: A two-edged sword in the melanocytic system

Improving Cancer Therapeutics by Molecular Profiling

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