Kinase mutations in human disease: interpreting genotype–phenotype relationships

Lahiry, Piya; Torkamani, Ali; Schork, Nicholas J.; Hegele, Robert A.

doi:10.1038/nrg2707

Cited by 339 publications

(282 citation statements)

References 117 publications

Supporting

Mentioning

280

Contrasting

Unclassified

Order By: Relevance

“…This uncontrolled growth of cells can metastasize and cause significant morbidity and mortality (Lahiry et al, 2010). Hence, altered gene expressions particularly in oncogenes and tumor suppressor genes play an important role in the development of carcinogenesis (Planchard et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

RNA interference-mediated URG4 gene silencing diminishes cyclin D1 mRNA expression in HepG2 cells

Şatıroğlu-Tufan¹,

Dodurga²,

D³

et al. 2010

Genet. Mol. Res.

View full text Add to dashboard Cite

ABSTRACT. Up-regulated gene 4 (URG4), stimulated by HBxAg, is a novel gene located on chromosome 7 (7p13). The full-length URG4 clone is 3.607 kb and encodes a polypeptide of 922 amino acids, with a molecular weight of 104 kDa (GeneID: 55665). It promotes cell growth, growth factor-independent survival, and anchorage-independent growth in HepG2 cells, and it accelerates tumor formation in nude mice. Hence, URG4 may be a natural effector of HBxAg and a putative oncogene that contributes to multi-step hepatocarcinogenesis. Cyclin D1 is frequently over-expressed in hepatocellular carcinoma, exhibiting a number of malignant phenotypes. We found that down-regulation of URG4 through RNA interference-mediated silencing suppressed cell proliferation in HepG2 cells. Over-expression of URG4 up-regulated cyclin D1 mRNA expression, whereas RNA interference-mediated URG4 silencing diminished cyclin D1 mRNA expression in HepG2 cells. The data suggest that URG4 may play an important role in the development of hepatocellular carcinoma by partially regulating the expression of cyclin D1 and has potential for use as a therapeutic target for hepatocellular carcinoma.

show abstract

Section: Introductionmentioning

confidence: 99%

RNA interference-mediated URG4 gene silencing diminishes cyclin D1 mRNA expression in HepG2 cells

Şatıroğlu-Tufan¹,

Dodurga²,

D³

et al. 2010

Genet. Mol. Res.

View full text Add to dashboard Cite

show abstract

“…Independently of direct HIF-1α/HIF-2α-driven transcriptional activation, hypoxia exerts a strong impact on members of the ErbB family RTKs that consists of EGFR/ErbB1, HER2 /ErbB2, HER3/ErbB3 and HER4/ErbB4 [71] whose aberrant activation by EGF family of growth factors is strongly associated with tumorigenesis, invasion and metastasis [72] Deregulated activity of ErbB receptors due to gene amplification, overexpression or mutations in numerous types of human cancers is tightly associated with poor prognosis and resistance to various treatment modalities [73][74][75].…”

Section: Hif-independent Regulation Of Erbb Igfr and Fgfr Family Memmentioning

confidence: 99%

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

Glück

Aebersold

Zimmer

et al. 2015

The International Journal of Biochemistry & Cell Biology

View full text Add to dashboard Cite

“…Dysregulation leading to either loss or gain of kinase activity may result in variety of disorders including cancer, inflammation, infection, and neurodegeneration (3)(4)(5), making development of compounds for modulating kinase activity an important therapeutic strategy (6).…”

Section: Introductionmentioning

confidence: 99%

Clustering of the structures of protein kinase activation loops: A new nomenclature for active and inactive kinase structures

Modi

2018

Preprint

View full text Add to dashboard Cite

Targeting protein kinases is an important strategy for intervention in cancer. Inhibitors are directed at the conserved active conformation or a variety of inactive conformations. While attempts have been made to classify these conformations, a structurally rigorous catalogue of states has not been achieved. The kinase activation loop is crucial for catalysis and begins with the conserved DFGmotif (Asp-Phe-Gly). This motif is observed in two major classes of conformations, DFGin -an ensemble of active and inactive conformations where the Phe residue is in contact with the C-helix of the N-terminal lobe, and DFGout -an inactive form where Phe occupies the ATP site exposing the C-helix pocket. We have developed a clustering of kinase conformations based on the backbone dihedral angles of the sequence X-D-F, where X is the residue before the DFGmotif, and the DFG-Phe side-chain rotamer, utilizing a density-based clustering algorithm. We have identified 8 distinct conformations and labeled them based on their Ramachandran regions (A=alpha, B=beta, L=left) and the Phe rotamer (minus, plus, trans). Our clustering divides the DFGin group into six clusters including 'BLAminus,' which contains active structures, and two common inactive forms, 'BLBplus' and 'ABAminus.' DFGout structures we have are predominantly in the 'BBAminus' conformation, which is essentially required for binding Type II inhibitors. Structural features such as the C-helix position and the overall activation loop conformation are strongly associated with our clusters. Our structurally intuitive nomenclature will aid in understanding the conformational dynamics of these proteins and structure-based development of kinase drugs.

show abstract

Kinase mutations in human disease: interpreting genotype–phenotype relationships

Cited by 339 publications

References 117 publications

RNA interference-mediated URG4 gene silencing diminishes cyclin D1 mRNA expression in HepG2 cells

RNA interference-mediated URG4 gene silencing diminishes cyclin D1 mRNA expression in HepG2 cells

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

Clustering of the structures of protein kinase activation loops: A new nomenclature for active and inactive kinase structures

Contact Info

Product

Resources

About