H-ras gene mutations in salivary gland mucoepidermoid carcinomas

Yoo, Jinyoung; Robinson, Robert A.

doi:10.1002/(sici)1097-0142(20000201)88:3<518::aid-cncr4>3.0.co;2-w

Cited by 38 publications

(27 citation statements)

References 15 publications

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“…Studies on salivary gland tumors demonstrated that aside from overexpression of the c-ERBB2 gene product [12,13] and alterations in H-ras and p53 gene expression [14,15] in a small subset of tumor samples, no other specific molecular marker has been associated with these tumors. The MECT1-MAML2 fusion oncogene has been detected in 75% of salivary gland mucoepidermoid cancers [5,6,16], suggesting that it is a useful diagnostic marker for this tumor type, particularly in cases with atypical or higher grade morphology.…”

Section: Discussionmentioning

confidence: 97%

Mammalian mastermind like 2 11q21 gene rearrangement in bronchopulmonary mucoepidermoid carcinoma

et al. 2009

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Section: Discussionmentioning

confidence: 97%

Mammalian mastermind like 2 11q21 gene rearrangement in bronchopulmonary mucoepidermoid carcinoma

et al. 2009

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“…For example, such differences may underlie the observations that activated Nras is associated with myeloid malignancies (66), germ cell tumors (34), congenital melanocytic nevi, and cutaneous melanomas derived from neural crest, but not mucosal melanomas, which are not derived from neural crest (7,93). In addition, Hras activation is associated with tumorigenesis of the bladder (45,79,100) and salivary gland (97,98), tissues that arise from an ontogenetic transitional zone, a region where endoderm and ectoderm meet. Notably, the expression of activated Hras, Nras, or Kras in PCC4 cells, which can give rise to mesenchymal (but not endodermal) cells in culture, does not result in an observable phenotype.…”

Section: Discussionmentioning

confidence: 99%

Activated Kras, but Not Hras or Nras, May Initiate Tumors of Endodermal Origin via Stem Cell Expansion

Quinlan

Quatela

Philips

et al. 2008

Molecular and Cellular Biology

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The three closely related human Ras genes, Hras, Nras, and Kras, are all widely expressed, engage a common set of downstream effectors, and can each exhibit oncogenic activity. However, the vast majority of activating Ras mutations in human tumors involve Kras. Moreover, Kras mutations are most frequently seen in tumors of endodermally derived tissues (lung, pancreas, and colon), suggesting that activated Kras may affect an endodermal progenitor to initiate oncogenesis. Using a culture model of retinoic acid (RA)-induced stem cell differentiation to endoderm, we determined that while activated HrasV12 promotes differentiation and growth arrest in these endodermal progenitors, KrasV12 promotes their proliferation. Furthermore, KrasV12-expressing endodermal progenitors fail to differentiate upon RA treatment and continue to proliferate and maintain stem cell characteristics. NrasV12 neither promotes nor prevents differentiation. A structure-function analysis demonstrated that these distinct effects of the Ras isoforms involve their variable C-terminal domains, implicating compartmentalized signaling, and revealed a requirement for several established Ras effectors. These findings indicate that activated Ras isoforms exert profoundly different effects on endodermal progenitors and that mutant Kras may initiate tumorigenesis by expanding a susceptible stem/progenitor cell population. These results potentially explain the high frequency of Kras mutations in tumors of endodermal origin.

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“…H-Ras activation is observed in a small but substantial percentage of human cancer. Approximately 20% of samples from salivary gland tumors and bladder cancer contain H-Ras mutations 101,102 . Germline mutations of HRas have been identified in approximately 90% of people with Costello syndrome, a genetic disorder associated with characteristic craniofacial features, developmental delay and cardiac and skeletal anomalies [103][104][105] .…”

Section: Toward Rational Uses Of Ftismentioning

confidence: 99%

Therapeutic intervention based on protein prenylation and associated modifications

et al. 2006

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In eukaryotic cells, a specific set of proteins are modified by C-terminal attachment of 15-carbon farnesyl groups or 20-carbon geranylgeranyl groups that function both as anchors for fixing proteins to membranes and as molecular handles for facilitating binding of these lipidated proteins to other proteins. Additional modification of these prenylated proteins includes C-terminal proteolysis and methylation, and attachment of a 16-carbon palmitoyl group; these modifications augment membrane anchoring and alter the dynamics of movement of proteins between different cellular membrane compartments. The enzymes in the protein prenylation pathway have been isolated and characterized. Blocking protein prenylation is proving to be therapeutically useful for the treatment of certain cancers, infection by protozoan parasites and the rare genetic disease Hutchinson-Gilford progeria syndrome.Isoprenoids are lipids made of five-carbon blocks, and they constitute one of the main classes of natural products. A subset of isoprenoids called prenyl groups are found on a variety of biological substances, including proteins. Prenylated proteins and peptides are found in most (if not all) eukaryotes. They arise from the post-translational attachment of 15-carbon farnesyl or 20-carbon geranylgeranyl groups to the C-terminal segment of proteins. Protein prenyl groups not only are hydrophobic elements that bind proteins to membranes, but, at least in some cases, they also function as molecular handles that bind to hydrophobic grooves on the surface of soluble protein factors; these factors then remove the prenylated protein from the membrane in a regulated manner. NIH Public Access Author ManuscriptNat Chem Biol. Author manuscript; available in PMC 2010 June 28. Published in final edited form as:Nat Chem Biol. 2006 October ; 2(10): 518-528. doi:10.1038/nchembio818. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptProtein prenylation has been vigorously studied over the past ~15 years because it is found on several signaling proteins (including heterotrimeric G proteins) that connect cell surface receptors to intracellular effectors, and also on Ras proteins, one of the most common oncoproteins found in human tumors. Ras proteins serve as molecular switches at cellular membranes to control propagation of growth signals from cell surface receptors to nuclear transcription factors. Because Ras mutations are important in many human cancers, there has been extensive focus on Ras prenylation. Discovery of protein prenyl groups and structural varietiesThe first reports of prenylated proteins and peptides described the secreted pheromone peptides from jelly fungi 1,2 , whose structure resembles that of the well-known a-factor mating pheromone from baker's yeast (Saccharomyces cerevisiae), which contains a cysteine methylester farnesylated at the C terminus 3 . In the 1980s, studies on the timing of cholesterol biosynthesis with respect to the cell cycle in human cells led to the discovery that a compound deriv...

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H-ras gene mutations in salivary gland mucoepidermoid carcinomas

Cited by 38 publications

References 15 publications

Mammalian mastermind like 2 11q21 gene rearrangement in bronchopulmonary mucoepidermoid carcinoma

Mammalian mastermind like 2 11q21 gene rearrangement in bronchopulmonary mucoepidermoid carcinoma

Activated Kras, but Not Hras or Nras, May Initiate Tumors of Endodermal Origin via Stem Cell Expansion

Therapeutic intervention based on protein prenylation and associated modifications

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