DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers

Lockwood, William W.; Chari, Raj; Coe, Bradley P.; Girard, Luc; MacAulay, Calum; Lam, Stephen; Gazdar, Adi F.; Minna, John D.; Lam, Wan L.

doi:10.1038/onc.2008.98

Cited by 106 publications

(131 citation statements)

References 43 publications

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“…Indeed, a recent study on CDK5-mediated regulation of the PIKE-A-Akt pathway suggests an important clue to the association of CDK5 with tumorigenesis, as the accumulation of phosphorylated PIKE-A (PI3-kinase enhancer), a recently identified GTP-binding protein shown to regulate the PI3K-Akt pathway and activation of Akt in the nucleus of glioblastoma cell, is a CDK5-dependent activity, 23 suggesting possible association of CDK5 with non-neuronal cell survival. This was further supported by another study that showed the overexpression of CDK5, along with the other downstream components of the EGFR-family signaling pathway, such as AKT1 and SHC1, as a direct result of gene amplification, specifically in lung cancer cells, 17 signifying that the alteration of the CDK5 gene may play a causal role in the development of lung cancer. In this study, we evaluated the associations between three newly found SNPs (À904 G4A, À270 C4G and À238 A4C) in the promoter region of the CDK5 gene and the risk for lung cancer.…”

Section: Discussionmentioning

confidence: 63%

“…16 Frequent amplification and overexpression of the CDK5 gene along with multiple epidermal growth factor receptor (EGFR)-family-signaling pathway components, including SHC1, AKT1 and MYC, was recently discovered in non-small cell lung cancer (NSCLC). 17 As it has been known earlier that CDK5/p35 activation by neuregulin subsequently activates PI3K and Akt through ErbB3 and ErbB2 receptors in cultured cortical neurons, 18 the activation of CDK5, along with the other genes, may play a role in NSCLC tumorigenesis.…”

Section: Introductionmentioning

confidence: 96%

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Single-nucleotide polymorphisms in the promoter of the CDK5 gene and lung cancer risk in a Korean population

et al. 2009

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Cyclin-dependent kinase 5 (CDK5), a proline-directed serine/threonine kinase, which was originally known for its regulatory role in neuronal activities, has recently been suggested to play a role in extraneuronal activities. For example, a recent study detected overexpression of the CDK5 gene in non-small-cell lung cancer. Therefore, in order to explore the association of the CDK5 gene with lung cancer risk in a Korean population, the genotypes of the CDK5 promoter region were determined in 407 lung cancer patients and 402 normal participants. The result showed that the À904 G4A genotype affected susceptibility to lung cancer risk (odd ratios (OR)¼1.53, 95% confidence interval (CI)¼1.02-2.32). Furthermore, subsequent haplotype analysis of three single-nucleotide polymorphism (SNP) regions suggested that the A-G-C haplotype was associated with a higher overall risk of lung cancer (OR¼1.59, 95% CI¼1.16-2.18). These results suggest that CDK5 promoter polymorphisms contribute to the genetic susceptibility to lung cancer in the Korean population.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 96%

Single-nucleotide polymorphisms in the promoter of the CDK5 gene and lung cancer risk in a Korean population

et al. 2009

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“…Overexpression of cdk5 has been shown in lung cancer (20). The single-nucleotide polymorphisms in the cdk5 promoter was also found and correlated with an increased risk of lung cancer (18).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Androgen Receptor and Prostate Cancer Growth by Cyclin-dependent Kinase 5

Hsu

Chen

Chiang

et al. 2011

Journal of Biological Chemistry

112

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Prostate cancer is the most frequently diagnosed male malignancy. The normal prostate development and prostate cancer progression are mediated by androgen receptor (AR). Recently, the roles of cyclin-dependent kinase 5 (Cdk5) and its activator, p35, in cancer biology are explored one after another. We have previously demonstrated that Cdk5 may regulate proliferation of thyroid cancer cells. In addition, we also identify that Cdk5 overactivation can be triggered by drug treatments and leads to apoptosis of prostate cancer cells. The aim of this study is to investigate how Cdk5 regulates AR activation and growth of prostate cancer cells. At first, the data show that Cdk5 enables phosphorylation of AR at Ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of AR proteins. The Cdk5-dependent AR stabilization causes accumulation of AR proteins and subsequent activation. Besides, the positive regulations of Cdk5-AR on cell growth are also determined in vitro and in vivo. S81A mutant of AR diminishes its interaction with Cdk5, reduces its nuclear localization, fails to stabilize its protein level, and therefore, decreases prostate cancer cell proliferation. Prostate carcinoma specimens collected from 177 AR-positive patients indicate the significant correlations between the protein levels of AR and Cdk5 or p35. These findings demonstrate that Cdk5 is an important modulator of AR and contributes to prostate cancer growth. Therefore, Cdk5-p35 may be suggested as diagnostic and therapeutic targets for prostate cancer in the near future.Prostate cancer is a commonly diagnosed malignancy in men, and androgen plays an important role in its early development (1). Androgen deprivation has been considered as a common therapy for androgen-dependent prostate cancer. However, the existing cancer cells eventually become hormone-refractory, and the following therapy usually gets into scrapes. The androgen receptor (AR), 2 which belongs to the steroid receptor family and plays pivotal roles in the development of the prostate gland and the pathogenic progression of prostate cancer. High levels of AR expression along with its target genes have been reported in hormone-refractory prostate cancer cells, suggesting that AR signaling is activated regardless of the levels of serum androgen (2). A study analyzing consensus sequences of phosphorylation indicates that AR contains more than 40 predicted phosphorylation sites (3). Ser-81 of the AR N terminus is the most intensely phosphorylated site in response to androgen binding (4). The latest report reveals the relevance of Ser-81 phosphorylation and AR promoter selectivity as well as cell growth (5). Our recent work also shows the increase of Ser-81 phosphorylation of AR in the androgen-independent LNCaP sub-line (6). Fu et al. (7) proposed that the phosphorylation consensus sequence (SPRT) of cyclin-dependent kinase 5 (Cdk5) corresponds with the sequence around AR Ser-81. Although AR was reported as substrates for Cdk9 (5) as well as Cdk1 (8), whi...

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“…(F) RBPJ mRNA expression in normal bronchial epithelium collected from healthy individuals (n = 67) versus non-small cell lung carcinoma (n = 111; Bild et al, 2006;Lockwood et al, 2010). (G) Analysis of lung cancers of mixed type with RBPJ genomic copy loss (n = 14) versus no loss (n = 30) with paired mRNA expression and aCGH data (Lockwood et al, 2008(Lockwood et al, , 2010. (H) Analysis of lung cancers from G broken down into tumor subtypes; adenocarcinoma RBPJ genomic loss (n = 6) versus no loss (n = 19); squamous cell carcinoma RBPJ genomic loss (n = 8) versus no loss (n = 11; Lockwood et al, 2008Lockwood et al, , 2010.…”

Section: Rbpj Is Frequently Lost In Human Cancersmentioning

confidence: 99%

“…(G) Analysis of lung cancers of mixed type with RBPJ genomic copy loss (n = 14) versus no loss (n = 30) with paired mRNA expression and aCGH data (Lockwood et al, 2008(Lockwood et al, , 2010. (H) Analysis of lung cancers from G broken down into tumor subtypes; adenocarcinoma RBPJ genomic loss (n = 6) versus no loss (n = 19); squamous cell carcinoma RBPJ genomic loss (n = 8) versus no loss (n = 11; Lockwood et al, 2008Lockwood et al, , 2010. (I) Analysis of RBPJ mRNA expression and genomic copy number in TCGA lung cancer adenocarcinomas (RBPJ genomic loss [n = 15] versus no loss [n = 114]) and squamous cell carcinomas (RBPJ genomic loss [n = 77] versus no loss [n = 101]; Cerami et al, 2012;Lockwood et al, 2012;Gao et al, 2013).…”

Section: Rbpj Is Frequently Lost In Human Cancersmentioning

confidence: 99%

Loss of the Notch effector RBPJ promotes tumorigenesis

Kulic¹,

Robertson²,

Chang³

et al. 2014

J Cell Biol

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DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers

Cited by 106 publications

References 43 publications

Single-nucleotide polymorphisms in the promoter of the CDK5 gene and lung cancer risk in a Korean population

Single-nucleotide polymorphisms in the promoter of the CDK5 gene and lung cancer risk in a Korean population

Regulation of Androgen Receptor and Prostate Cancer Growth by Cyclin-dependent Kinase 5

Loss of the Notch effector RBPJ promotes tumorigenesis

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