Raf kinase inhibitor protein: mechanism of loss of expression and association with genomic instability

2008 ◽  
Vol 61 (4) ◽  
pp. 524-529 ◽  
Author(s):  
F Al-Mulla ◽  
S Hagan ◽  
W Al-Ali ◽  
S P Jacob ◽  
A I Behbehani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Chromosomal Instability ◽  
Cultured Cells ◽  
Kinase Inhibitor ◽  
Methylation Status ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Metastasis Suppressor ◽  
Metastatic Progression ◽  
Raf Kinase

Aims:Raf kinase inhibitory protein (RKIP; also known as PEBP, for phosphatidylethanolamine-binding protein) is an endogenous inhibitor of the Raf– MAPK kinase (MEK)–MAP kinase pathway. It has emerged as a significant metastasis suppressor in a variety of human cancers including colorectal cancer (CRC) and was recently shown to regulate the spindle checkpoint in cultured cells. This study aims at correlating RKIP expression with chromosomal instability in colorectal cancer samples and identifies possible mechanisms of RKIP loss.Methods:Chromosomal instability was assessed using metaphase-based comparative genomic hybridisation (CGH) and loss of heterozygosity (LOH) in 65 cases with microsatellite stable CRC and correlated with RKIP expression. Methyl-specific PCR was used on DNA extracted from 82 cases with CRC to determine CpG methylation status at the RKIP promoter and the results correlated with RKIP protein expression.Results:We demonstrate for the first time that in microsatellite stable (MSS) CRC, the number of chromosomal losses is inversely proportional to RKIP expression levels. We also show that methylation of the RKIP promoter is a major mechanism by which RKIP expression is silenced in CRC.Conclusions:RKIP loss by hypermethylation of its promoter could have a significant influence on colorectal cancer aneuploidy, which might explain its association with metastatic progression.

scholarly journals Targeting Raf Kinase Inhibitory Protein Regulation and Function

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 306 ◽  
Author(s):  
Ali Yesilkanal ◽  
Marsha Rosner
Keyword(s):  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Signaling Networks ◽  
Metastasis Suppressor ◽  
Metastatic Progression ◽  
Inhibitory Protein ◽  
Raf Kinase ◽  
Raf Kinase Inhibitory Protein ◽  
And Function

Raf Kinase Inhibitory Protein (RKIP) is a highly conserved kinase inhibitor that functions as a metastasis suppressor in a variety of cancers. Since RKIP can reprogram tumor cells to a non-metastatic state by rewiring kinase networks, elucidating the mechanism by which RKIP acts not only reveals molecular mechanisms that regulate metastasis, but also represents an opportunity to target these signaling networks therapeutically. Although RKIP is often lost during metastatic progression, the mechanism by which this occurs in tumor cells is complex and not well understood. In this review, we summarize our current understanding of RKIP regulation in tumors and consider experimental and computational strategies for recovering or mimicking its function by targeting mediators of metastasis.

scholarly journals Current Status of Raf Kinase Inhibitor Protein (RKIP) in Lung Cancer: Behind RTK Signaling

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 442 ◽  
Author(s):  
Ana Raquel-Cunha ◽  
Diana Cardoso-Carneiro ◽  
Rui M. Reis ◽  
Olga Martinho
Keyword(s):  
Lung Cancer ◽  
Intracellular Signaling ◽  
Kinase Inhibitor ◽  
Egfr Inhibitors ◽  
Current Status ◽  
Tyrosine Kinase Domain ◽  
Metastasis Suppressor ◽  
Inhibitory Protein ◽  
Suppressor Activity ◽  
Raf Kinase

Lung cancer is the most deadly neoplasm with the highest incidence in both genders, with non-small cell lung cancer (NSCLC) being the most frequent subtype. Somatic mutations within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are key drivers of NSCLC progression, with EGFR inhibitors being particularly beneficial for patients carrying the so-called “EGFR-sensitizing mutations”. However, patients eventually acquire resistance to these EGFR inhibitors, and a better knowledge of other driven and targetable proteins will allow the design of increasingly accurate drugs against patients’ specific molecular aberrations. Raf kinase inhibitory protein (RKIP) is an important modulator of relevant intracellular signaling pathways, including those controlled by EGFR, such as MAPK. It has been reported that it has metastasis suppressor activity and a prognostic role in several solid tumors, including lung cancer. In the present review, the potential use of RKIP in the clinic as a prognostic biomarker and predictor of therapy response in lung cancer is addressed.

scholarly journals Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer

The Prostate ◽  
2006 ◽  
Vol 66 (3) ◽  
pp. 248-256 ◽  
Author(s):  
Zheng Fu ◽  
Yasuhide Kitagawa ◽  
Ronglai Shen ◽  
Rajal Shah ◽  
Rohit Mehra ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prognostic Marker ◽  
Kinase Inhibitor ◽  
Suppressor Gene ◽  
Metastasis Suppressor ◽  
Metastasis Suppressor Gene ◽  
Inhibitor Protein ◽  
Raf Kinase ◽  
Raf Kinase Inhibitor Protein

scholarly journals Promoter Methylation Precedes Chromosomal Alterations in Colorectal Cancer Development

2006 ◽  
Vol 28 (5-6) ◽  
pp. 247-257 ◽  
Author(s):  
Sarah Derks ◽  
Cindy Postma ◽  
Peter T. M. Moerkerk ◽  
Sandra M. van den Bosch ◽  
Beatriz Carvalho ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Promoter Methylation ◽  
Chromosomal Abnormalities ◽  
Methylation Status ◽  
Colorectal Carcinogenesis ◽  
Cancer Development ◽  
Comparative Genomic ◽  
Early Event ◽  
Chromosomal Alterations ◽  
Normal Tissues

Background: Colorectal cancers are characterized by genetic and epigenetic alterations. This study aimed to explore the timing of promoter methylation and relationship with mutations and chromosomal alterations in colorectal carcinogenesis. Methods: In a series of 47 nonprogressed adenomas, 41 progressed adenomas (malignant polyps), 38 colorectal carcinomas and 18 paired normal tissues, we evaluated promoter methylation status of hMLH1, O6MGMT, APC, p14ARF, p16INK4A, RASSF1A, GATA-4, GATA-5, and CHFR using methylation-specific PCR. Mutation status of TP53, APC and KRAS were studied by p53 immunohistochemistry and sequencing of the APC and KRAS mutation cluster regions. Chromosomal alterations were evaluated by comparative genomic hybridization. Results: Our data demonstrate that nonprogressed adenomas, progressed adenomas and carcinomas show similar frequencies of promoter methylation for the majority of the genes. Normal tissues showed significantly lower frequencies of promoter methylation of APC, p16INK4A, GATA-4, and GATA-5 (P-values: 0.02, 0.02, 1.1×10−5 and 0.008 respectively). P53 immunopositivity and chromosomal abnormalities occur predominantly in carcinomas (P values: 1.1×10−5 and 4.1×10−10). Conclusions: Since promoter methylation was already present in nonprogressed adenomas without chromosomal alterations, we conclude that promoter methylation can be regarded as an early event preceding TP53 mutation and chromosomal abnormalities in colorectal cancer development.

Sign in / Sign up

Export Citation Format

Share Document