Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

The Ras family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) represents one of the main components of intracellular signal transduction required for normal cardiac growth, but is also critically involved in the development of cardiac hypertrophy and heart failure. The present review provides an update on the role of the H-, K- and N-Ras genes and their related pathways in cardiac diseases. We focus on cardiac hypertrophy and heart failure, where Ras has been studied the most. We also review other cardiac diseases, like genetic disorders related to Ras. The scope of the review extends from fundamental concepts to therapeutic applications. Although the three Ras genes have a nearly identical primary structure, there are important functional differences between them: H-Ras mainly regulates cardiomyocyte size, whereas K-Ras regulates cardiomyocyte proliferation. N-Ras is the least studied in cardiac cells and is less associated to cardiac defects. Clinically, oncogenic H-Ras causes Costello syndrome and facio-cutaneous-skeletal syndromes with hypertrophic cardiomyopathy and arrhythmias. On the other hand, oncogenic K-Ras and alterations of other genes of the Ras-Mitogen-Activated Protein Kinase (MAPK) pathway, like Raf, cause Noonan syndrome and cardio-facio-cutaneous syndromes characterized by cardiac hypertrophy and septal defects. We further review the modulation by Ras of key signaling pathways in the cardiomyocyte, including: (i) the classical Ras-Raf-MAPK pathway, which leads to a more physiological form of cardiac hypertrophy; as well as other pathways associated with pathological cardiac hypertrophy, like (ii) The SAPK (stress activated protein kinase) pathways p38 and JNK; and (iii) The alternative pathway Raf-Calcineurin-Nuclear Factor of Activated T cells (NFAT). Genetic alterations of Ras isoforms or of genes in the Ras-MAPK pathway result in Ras-opathies, conditions frequently associated with cardiac hypertrophy or septal defects among other cardiac diseases. Several studies underline the potential role of H- and K-Ras as a hinge between physiological and pathological cardiac hypertrophy, and as potential therapeutic targets in cardiac hypertrophy and failure. Highlights - The Ras (Rat Sarcoma) gene family is a group of small G proteins - Ras is regulated by growth factors and neurohormones affecting cardiomyocyte growth and hypertrophy - Ras directly affects cardiomyocyte physiological and pathological hypertrophy - Genetic alterations of Ras and its pathways result in various cardiac phenotypes? - Ras and its pathway are differentially regulated in acquired heart disease - Ras modulation is a promising therapeutic target in various cardiac conditions.

Study on Association between an H-RAS Gene Polymorphism and Gastric Cancer Development / 대한소화기학회지

BACKGROUND/AIMS: Oncogenic RAS gene mutations have been frequently observed in many tumor types, and their associations with various cancers were reported. This study was conducted to evaluate the association between H-RAS T81C polymorphism and gastric cancer development. METHODS: H-RAS T81C polymorphism was genotyped in 321 chronic gastritis (ChG) and 151 gastric cancer (GC) patients using GoldenGate(R) Assay kit. Logistic regression analysis adjusted for age and gender was performed to identify the differences of genotype and allele distributions between the each group. RESULTS: All ChG and GC patients were in Hardy-Weinberg equilibrium. When the frequencies of H-RAS T81C genotype in each group were compared, the homozygous type of major allele TT was more frequent in GC group (62.9%) than ChG group (57.3%), while the frequencies of heterozygous type TC and homozygous type of minor allele CC were higher in ChG group than GC group (39.3% vs. 33.8%, 3.4% vs. 3.3%, respectively). In the results of logistic regression analyses adjusted for age and gender, the odds ratios were 0.845 (0.604-1.182), 0.799 (0.556-1.147), 0.741 (0.493-1.114) and 1.094 (0.366-3.270) for allele, codominant, dominant and recessive models, respectively. However, significant difference was not observed between two groups in any models. CONCLUSIONS: H-RAS T81C polymorphism was not associated with gastric cancer development in a Korean population.

A PCR-RFLP method for the detection of activated H-ras oncogene with a point mutation at codon 12 and 61

To investigate the incidence of the H-ras gene activation in bladder tumor and the feasibility of using urinary washout samples for screening, a series of 33 human bladder tumors and their preoperatively collected urinary washout samples were screened using a mutant specific PCR-RFLP (polymerase chain-restriction fragment length polymorphism) to detect a point mutation of the H-ras gene. Five tumors were found to harbor H-ras mutations where two tumors had a glycine to valine (G-->T) change in codon 12 and three tumors had a glutamine to lysine (C-->A) change in codon 61, respectively. Moreover, we could also detect the same point mutations of the H-ras gene in corresponding urine washout samples. The incidence of H-ras mutation in Korean bladder cancer was estimated at approximately 15.2%. In conclusion, a mutant specific PCR-RFLP method for the detection of H-ras gene mutation is useful for screening or postoperative follow-up of bladder tumor due to its simplicity and high specificity even in urinary samples.