• 생명과학회지
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• 제20권2호
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• pp.202-207
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• 2010

Ras 유전자는 30%의 인간암에서 변이가 발견되며 세 종류의 isoform, H-Ras, K-Ras 및 N-Ras로 구성되어 있다. Ras 단백질의 CAAX motif에 farnesylation과 같은 번역 후 변형은 Ras의 활성에 필수 요소이다. 본 연구에서는 새로운 farnesyl transferase 억제제인 YH3938과 YH3945의 발암원성 H-Ras, K-Ras 및 N-Ras의 작용에 대한 영향을 조사하였다. YH3938과 YH3945는 발암원성 H-Ras에 의해 형질전환된 Rat2 세포의 증식과 형태 변화를 억제하였으나 K-Ras에 대해서는 효과가 없었다. N-Ras에 대해서는 약한 영향이 있었다. H-Ras와 N-Ras에 의한 SRE promoter 활성화는 YH3938과 YH3945에 의해 억제되었으나, K-Ras에는 영향이 없었다. Ras 단백질의 bandshift 분석을 통해 YH3938은 H-Ras와 N-Ras의 번역 후 변환을 억제하였으나, K-Ras에는 영향이 없었다. YH3945는 H-Ras의 변환에만 영향이 있었다. 결론적으로 YH3938과 YH3945는 H-Ras의 farnesylation을 억제하여 그 발암원성을 억제하며, YH3938은 N-Ras 작용을 농도의존적으로 억제하며, K-ras에 대해서는 영향이 없음을 알 수 있었다.

• Archives of Pharmacal Research
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• 제25권6호
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• pp.759-769
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• 2002

Mutated forms of ras are found in many human tumors and the rate of incidence is significantly higher in colon and pancreatic cancers. The protein product from the ras oncogene is a small G-protein, $p21^{ras}{\;}(Ras)$ that is known to playa key role in the signal transduction cascade and cell differentiation and proliferation. Mutated Ras is unable to regulate itself and remains constantly activated, leading to uncontrolled cell growth. The function of Ras in signal transduction requires its location near the growth factor receptor at the cell membrane. However, Ras does not have a transmembrane domain. Ras requires farnesylation to increase its hydrophobicity and subsequent plasma membrane association for its transforming activity. This key post-translational modification is catalyzed by the enzyme Ras farnesyltransferase (FTase), which transfers a farnesyl group from farnesylpyrophosphate to the C-terminal cysteine of the Ras protein. The requirement has focused attention on FTase as a target for therapeutic intervention. Selective inhibition of FTase will prevent Ras protein from association with the plasma membrane, leading to a disruption of oncogenic Ras function.

• Archives of Pharmacal Research
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• 제29권2호
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• pp.113-122
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• 2006

Among the effector molecules connected with the group of cell surface receptors, Ras proteins have essential roles in transducing extracellular signals to diverse intracellular events, by controlling the activities of multiple signaling pathways. For over 20 years since the discovery of Ras proteins, an enormous amount of knowledge has been accumulated as to how the proteins function in overlapping or distinct fashions. The signaling networks they regulate are very complex due to their multiple functions and cross-talks. Much attention has been paid to the pathological role of Ras in tumorigenesis. In particular, human tumors very frequently express Ras proteins constitutively activated by point mutations. Up to date, three members of the Ras family have been identified, namely H-Ras, K-Ras (A and B), and N-Ras. Although these Ras isoforms function in similar ways, many evidences also support the distinct molecular function of each Ras protein. This review summarizes differential functions of Ras and highlights the current view of the distinct signaling network regulated by each Ras for its contribution to the malignant phenotypic conversion of breast epithelial cells. Four issues are addressed in this review: (1) Ras proteins, (2) membrane localization of Ras, (3) effector molecules downstream of Ras, (4) Ras signaling in invasion. In spite of the accumulation of information on the differential functions of Ras, much more remains to be elucidated to understand the Ras-mediated molecular events of malignant phenotypic conversion of cells in a greater detail.

• BMB Reports
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• 제29권5호
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• pp.442-447
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• 1996

Mutations in codon 12, 13 and 61 of one of the three ras genes, H-ras, K-ras and N-ras, convert these genes into active oncogenes. The presence of H-ras gene mutations have important prognostic implications in various cancers. In this study, the H-ras gene mutations were investigated by two-step PCRRFLP in patients with bladder and stomach cancer. For the control experiments, T24 and SK2 cell lines were used. In a total of 36 bladder cancer patient cases, five (13.9%) mutations were found by this method. Of these, point 12 mutations were two (5.6%) cases and point 61 mutations were three (8.3%) cases. On the other hand, H-ras mutation was not found in 29 cases of stomach cancer. The results of the mutated H-ras gene confirmed by direct sequencing analysis were correlated well with PCR analysis. From the sensitivity test, the H-ras mutation was found to have about 0.2% of mutated DNA mingled in normal DNA. In conclusion, the H-ras mutation has a higher clinical Significance in bladder cancer than stomach cancer. Moreover the two-step PCR-RFLP method is sensitive, rapid and relatively simple for clinical work in detecting H-ras point mutations.

• ALGAE
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• 제35권4호
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• pp.325-335
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• 2020

A new diatom species, Mayamaea vietnamica sp. nov., is described from Cát Tiên National Park in Vietnam. This species was discovered and described from soil samples. Algae from soil ecosystems in Vietnam are almost unknown. The new species is described on the basis of an integrated approach with molecular and morphological data, and comparison with similar species. In terms of molecular data, 18S rDNA (including V4 domain), and partial rbcL plastid genes show M. vietnamica sp. nov. is most closely related to M. terrestris N. Abarca and R. Jahn, and together they form a monophyletic group relative to other members of the genus. M. vietnamica sp. nov. differs from other species in the genus by the number of striae and areolae in 10 ㎛, number of areolae per stria, as well as shape and presence or absence of axial and central areas.

• 한국동물생명공학회지
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• 제35권1호
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• pp.12-20
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• 2020

Cell adhesion plays an important role in the differentiation of the morphogenesis and the trophectoderm epithelium of the blastocyst. In the porcine embryo, CDH1 mediated adhesion initiates at compaction before blastocyst formation, regulated post-translationally via protein kinase C and other signaling molecules. Here we focus on muscle RAS oncogene homolog (M-RAS), which is the closest relative to the RAS related proteins and shares most regulatory and effector interactions. To characterize the effects of M-RAS on embryo compaction, we used gain- and loss-of-function strategies in porcine embryos, in which M-RAS gene structure and protein sequence are conserved. We showed that knockdown of M-RAS in zygotes reduced embryo development abilities and CDH1 expression. Moreover, the phosphorylation of ERK was also decreased in M-RAS KD embryos. Overexpression of M-RAS allows M-RAS KD embryos to rescue the embryo compaction and blastocyst formation. Collectively, these results highlight novel conserved and multiple effects of M-RAS during porcine embryo development.

• 생명과학회지
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• 제28권9호
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• pp.1100-1117
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• 2018

Ras superfamily에 속하는 monomeric small GTPase는 현재까지 170여 종이 알려져 있으며 이들은 세포 신호전달에 있어서 분자 스위치(molecular switch)로 작용하고 있다. Ras GTPase는 guanosine diphosphate (GDP)와 결합하여 불활성화 되거나 혹은 guanosine triphosphate (GTP)와 결합하여 활성화되는 guanosine nucleotide 결합단백질로서 세포내의 수많은 생리작용을 조절하고 있다. 즉, 쉬고 있던 불활성화 상태의 Ras-GDP는 외부 신호에 반응하여 활성화 된 guanine nucleotide exchange factor (GEF)에 의하여 활성형인 Ras-GTP상태로 전환되어 그 하류로 신호를 전달하는 효과기로 작용하게 된다. 신호전달을 마친 Ras-GTP는 다시 불활성형인 Ras-GDP로 전환되어야 하는데 Ras 자체의 GTPase 활성이 미약하여 RasGTPase activating protein (RasGAP)의 도움을 받아야만 한다. 이와 같이 Ras GTPase는 GEF와 GAP의 활성으로 세포 안의 스위치를 켜고 끄게 된다. 현재까지 알려진 인간 암(cancer)의 30% 이상이 돌연변이를 포함하는 Ras switch의 비정상적인 작동에 기인한다는 점이 밝혀져 있으므로 Ras GTPase의 구조와 생리적 기능에 대한 최근의 연구결과들을 요약하였다. 나아가 GTPase activating protein으로서의 기능을 상실한 RasGAP분자의 돌연변이는 세포 안의 Ras 스위치를 계속 켜 두는 상태인 Ras-GTP 상태를 유발함으로서 종국에는 암의 발생을 촉발하게 된다. 이에, 본고에서는 최근에 와서 tumor suppressor로서 알려지면서 암의 치료 표적단백질로 떠오르게 된 RasGAP의 인체생리학적 기능을 고찰하였다. 인간 게놈 안에는 RASA1, NF1, GAP1 family 및 SynGAP family 등에 속하는 14종의 RasGAP 분자들이 존재하는데 이들 GAP분자들의 이상과 인간 질병의 연관성에 대한 최근의 연구결과들에 대해 고찰하였다.

• BMB Reports
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• 제29권5호
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• pp.484-487
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• 1996

The matrix metalloproteinases (MMPs) are members of a unique family of proteolytic enzymes that degrade components of the extracellular matrix. Significant evidence has accumulated to directly implicate members of the MMPs in tumor invasion and metastasis formation. To investigate the correlation between ras oncogene and MMP gene expression in various tumor cells, we detected mRNAs for the ras, MMP-2 and MMP-9 (72 kD and 92 kD type IV collagenases, respectively) genes in nine human tumor cell lines. The ras gene was expressed in seven cell lines; MMP-2 in three; MMP-9 in two cell lines tested. There was no direct correlation between the ras oncogene and MMP expression. A clear difference in the mRNA expression between MMP-2 and MMP-9 was observed among the cell lines. As an approach to study the effect of the ras oncogene on metastasis, we examined the expressions of MMP-2 and MMP-9 in HT1080 cells transfected with the v-H-ras gene. MMP-9 expression was Significantly enhanced in the ras-transfected HT1080 cells compared with the nontransfectants while ras transfection did not affect the expression of MMP-2. These results suggest the possible inducing effect of the ras oncogene on the metastasis by activation of the MMP-9 gene in HT1080.

• BMB Reports
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• 제32권2호
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• pp.196-202
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• 1999

The existence of the Ras-independent signal transduction pathway of insulin leading to DNA synthesis was investigated in Rat-1 fibroblasts overexpressing human insulin receptor (HIRc-B) using the single-cell microinjection technique. Microinjection of a dominant-negative mutant $Ras^{N17}$ protein into quiescent HIRc-B cells inhibited the DNA synthesis stimulated by insulin. Microinjection of oncogenic H-$Ras^{V12}$ protein ($H-Ras^{V12}$) (0.1 mg/ml) induced DNA synthesis by 35%, whereas that of control-injected IgG was induced by 20%. When the marginal amount of oncogenic H-$Ras^{V12}$ protein was coinjected with a dominant-negative mutant of the H-Ras protein ($Ras^{N17}$), DNA synthesis was 35% and 74% in the absence and presence of insulin, respectively. This full recovery of DNA synthesis by insulin suggests the existence of the Ras-independent pathway. The same recovery was observed in the cells coinjected with either H-$Ras^{V12}$ plus H-$Ras^{N17}$ plus SH2 domain of the p85 subunit of PI3-kinase ($p85^{SH2-N}$) or H-$Ras^{V12}$ plus H-$Ras^{N17}$ plus interfering anti-Shc antibody. When co-injected with a dominant-negative H-$Ras^{N17}$, the DNA synthesis induced by the Ras-independent pathway was blocked. These results indicate that the Ras-independent pathway of insulin leading to DNA synthesis exists, bypassing the p85 of PI3-kinase and Shc protein, and requires Rac1 protein.

• Asian Pacific Journal of Cancer Prevention
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• 제13권12호
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• pp.6517-6521
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• 2012

To analyze the growth, proliferation, apoptosis, invasiveness and chemotherapy sensitivity of EC9706 cells after K-Ras gene silencing, an expression carrier pSilencer-siK-Ras was constructed, and the EC9706 cell line was transfected using a liposome technique. Six groups were established: Control, siRNA NC (transfected with empty vector pSilencer2.1); Ras siRNA (transfected with pSilencer-siK-Ras2); Paclitaxel; Paclitaxel + siRNA NC; and Ras siRNA + Paclitaxel. After the treatment, RT-PCR, Western blotting, MTT assay, flow cytometry and the Transwell technique were used to assess expression of K-Ras mRNA and protein in EC9706 cells, as well as cell growth, proliferation, apoptosis and invasiveness. The effect of Paclitaxel chemotherapy was also tested. pSilencer-siK-Ras2 effectively down-regulated expression of K-Ras mRNA and protein in EC9706 cells, growth being significantly inhibited. Flow cytometry indicated obvious apoptosis of cells in the experimental group, with arrest in the G1 phase; cell migration ability was also reduced. After pSilencer-siK-Ras2 transfection or the addition of Paclitaxel, EC9706 cells were suppressed to different extents; the suppressive effect was strengthened by combined treatment. The results suggested that RNAi-induced K-Ras gene silencing could enhance chemotherapy sensitivity of esophageal cancer.