• Title/Summary/Keyword: $p21^{ras}$ proteins

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p53 and K-ras Expression in Interstitial Lung Disease (간질성 폐질환에서 p53 및 K-ras 암표지자의 발현)

  • Oh, In-Jae;Kim, You-Il;Kim, Kyu-Sik;Yoo, Young-Kwon;Kim, Soo-Ok;Lee, Eun-Woo;Lim, Sung-Chul;Kim, Young-Chul;Park, Kyung-Ok;Park, Chang-Soo
    • Tuberculosis and Respiratory Diseases
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    • v.51 no.3
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    • pp.201-210
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    • 2001
  • Background : Approximately 10-13% of patients with interstitial lung disease(ILD) die of lung cancer, and patients with ILD have been reported to have a 7 fold higher incidence of lung cancer compared to the normal population. Recently, overexpression of the p53 and p21 proteins were observed in the epithelial cells from pathologic specimens of ILD. Overexpression of these proteins may result from chronic or recurrent DNA damage by unknown causes of inflammation. However, these proteins may also contribute to oncogenesis if other genetic alterations such as K-ras are superimposed. Methods : Immunohistochemical stains for p53 and K-ras proteins were performed with pathologic specimens from 38 cases with ILD(M/F : 27/11, mean agea : $54{\pm}10$ years) and from 10 control subjects. Results : The p53 protein was expressed in 21.1% (8/38 ILD cases) and K-ras protein expression was observed in 65.8% (25/38 ILD cases). However, neither p53 nor the K-ras protein staining was observed in the control subjects. Conclusion : A significant proportion of cases with ILD expressed the p53 and K-ras proteins in their bronchial epithelial cells. These proteins may be potentially oncogenic with the addition of further genetic alterations. However, to clarify the significance of these findings, further studies looking for correlations with the incidence of lung cancer and other genetic changes are needed.

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Purification and Characterization of Farnesyl Protein Transferase from Bovine Testis

  • Ryo, Kwon-Yul;Baik, Young-Jin;Yang, Chul-Hak
    • BMB Reports
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    • v.28 no.3
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    • pp.197-203
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    • 1995
  • Famesyl protein transferase involved in the first step of post-translational modification of $p21^{ras}$ proteins transfers the famesyl moiety from famesyl pyrophosphate to a cysteine residue in $p21^{ras}$ proteins. The enzyme was first purified 30,000-fold from bovine testis by use of 30~50% ammonium sulfate fractionation, DEAE-Sephacel ion exchange chromatography, Sephacryl S-300 gel filtration chromatography, Sephacryl S-200 gel filtration chromatography, and hexapeptide (Lys-Lys-Cys-Val-Ile-Met) affinity chromatography. The molecular weight of the purified enzyme was estimated to be ~100 kDa by gel filtration and SDS-polyacrylamide gels showed two closely spaced bands of ~50 kDa protein. These indicate that the enzyme consists of two nonidentical subunits, a and 13, which have slightly different molecular weights. The enzyme was inhibited by hexapeptide (Lys-Lys-Cys-Val-Ile-Met), which acted as an alternative substrate that competed for famesylation. Kinetic analysis by measuring initial velocities showed that famesyl protein transferase is a very slow enzyme. EDTA-treated famesyl protein transferase showed little activity with $Mg^{2+}$ or $Zn^{2+}$ alone, but required both $Mg^{2+}$ and $Zn^{2+}$ for the catalytic activity.

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신경성장기전 및 치료제개발

  • 양성일
    • Proceedings of the Korean Society of Applied Pharmacology
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    • 1993.11a
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    • pp.28-33
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    • 1993
  • Regulation of nerve growth factor (NGF)-induced neuronal differentiation by GTPase activating protein(GAP) and its mechanism were investigated in rat pheochromocytoma cell line, PCl2. Overexpression of GAP caused the delay in the onset of neurite outgrowth of PCl2 eel Is in response to NGF. GAP has been known to inhibit p21$\^$ras/, the activated form of which induces neuronal differentiation. Therefore, the activity of p21$\^$ras/ was compared in control cells and cells overexpressing GAP indirectly by measuring the activities of B-Raf and MAP kinase that are known to be positively regulated by p21$\^$ras/. Surprisingly, NGF-induced activities of these two proteins were the same in control eells and GAP-overexpressing cells. Activities of Trk, PLC-r and SMC that act at a site upstream to p21$\^$ras/ in NGF signal transduction pathway were not also affected by GAP overexpression. Interestingly, however, the extent of tyrosine phosphorylation of SNT was found to be remarkably low in cells overexpressing GAP. It has been shown previously that neurotrophins and not mitogens induce SNT tyrosine phosphorylation in PCl2 cells. Thus it is possible that the timing of NGF-induced neuronal differntiation may be in part regulated by SNT and the slower onset of neurite outgrowth in cells overexpressing GAP may be through the inhibition of SNT by GAP.

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F93-A: A Inhibitor of Farnesyl Protein Transferase from Aspergillus fumigatus KL93

  • Kwon, Byoung-Mog;Lee, Seung-Ho;Jeong, Tae-Sook;Kim, Sung-Uk;Son, Kwang-Hee;Park, Diol;Kim, Young-Kook;Nam, Ji-Youn;Bok, Song-Hae
    • Proceedings of the Korean Society of Applied Pharmacology
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    • 1995.04a
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    • pp.66-66
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    • 1995
  • Mutated forms of the ras oncogenes are associated with about 30% of human tumors. The ras genes encode 21KDa proteins, called p21 or Ras, that are associated with the plasma membrane. FPTase is a dimeric enzyme that catalyses the transfer of the farnesyl group from farnesyl pyrophosphate onto cysteine 186 at the C-terminus of the Ras protein. This is mandatory process for triggering ras oncogene toward tumor formation. Therefore, selective inhibitors of FPTase have the potential to be used as antitumorgenic agents.

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STUDY ON MUTATION OF RAS GENE IN DMBA INDUCED CARCINOMA OF HAMSTER BUCCAL POUCH (DMBA로 유도된 햄스터 협낭암종에서 ras 유전자 변이에 관한 연구)

  • Song, Sun-Chul;Kim, Kyung-Wook;Lee, Jae-Hoon;Kim, Chang-Jin
    • Journal of the Korean Association of Oral and Maxillofacial Surgeons
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    • v.26 no.6
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    • pp.581-590
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    • 2000
  • Alterations in the cellular genome affecting the expression or function of genes controlling cell growth and differentiation are considered to be the main cause of cancer. Over 30 oncogenes can be activated by insertional mutagenesis, single point mutations, chromosomal translocations and gene amplification. The ras oncogenes have been detected in $15{\sim}20%$ of human tumors that include some of the most common forms of human neoplasia and are known to acquire their transforming properties by single point mutations in two domains of their coding sequences, most commonly in codons 12 and 61. The ras gene family consists of three functional genes, N-ras, K-ras and H-ras which encode highly similar proteins of 188 or 189 amino acid residues generically known as P21. ras proteins have been shown to bind GTP and GTP, and possess intrinsic GTPase activity. Experimental study was performed to observe the mutational change of the ras gene family and apply the results to the clinical activity. 36 Golden Syrian Hamster each weighing $60{\sim}80g$ were used and painted with 0.5% DMBA by 3 times weekly on the right buccal cheek(experimental side) for 6, 8, 10, 12, 14 and 16 weeks. Left buccal cheek (control side) was treated with mineral oil as the same manner of the right side. The hamsters were sacrificed on the 6, 8, 10, 12, 14 & 16 weeks. Normal and tumor tissues from paraffin block were completely dissected by microdissection and DNA from both tissue were isolated by proteinase K/phenol/chloroform extraction. Segments of the K-ras and H-ras gene were amplified by PCR using the oligonucleotide primers corresponding to the homologous region (codon 12 and 61) of the hamster gene, and then confirmational change of ras genes was observed by SSCP and autosequencing analysis. The results were as follows : 1. Malignant lesion could be found in the experimental side from the experimental six weeks. 2. One hamster among six showed point mutation of the H-ras codon 12($G{\rightarrow}A$ transition) at the experimental 10 and 14 weeks. 3. One of six at 6 weeks, two of six at 8 weeks and one of six at 12 weeks revealed the confirmational change of the H-ras codon 61($A{\rightarrow}T$ transversion). 4. The incidence of point mutation of H-ras codon 12 and 61 were 5.5%(2 of 36) and 11%(4 of 36) respectively. 5. Point mutation of the K-ras could not be seen during the whole experimental period. Form the above results, these findings strongly support the concept that H-ras oncogenes may have the influence of the DMBA induced carcinoma of hamster buccal pouch.

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2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin Induces Recruitment of Shc/Cbl/Grb2/Sos Conplex in Early Signaling Pathway of CYP1A1 Induction in the Primary Culture of Hepatocytes

  • Kim, Bok-Ryang;Park, Rae-Kil;Kim, Dong-Hyun
    • Toxicological Research
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    • v.15 no.1
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    • pp.89-93
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    • 1999
  • 2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) is known to induce cytochrome p450 1A1 and to activate c-Src kinase and p21 Ras. This study examined the molecular interactions of adaptor proteins including Shc, Grb2, and Sos in rat primary hepatocytes and their relationship to the induction of CYP1A1 by TCDD. TCDD induced CYP1A1 level and EROD activity in a dose-dependent mode. Sos/Grb2 association isincreased by TCDDㅑㅜ a dose dependent mode. Tyrosine phosphorylated Shc, mainly p152, onloads to Grb2/Sos complex upon TCDD stimulation. The electrophoretic mobility shift of Sos is showed by TCDD. These results indicate that TCDD modulated the molecular interaction features of adaptor compoes proteins including Shc, Grb2, and Cnl in early signaling pathway of TCDD-mediated CYP 1A1 induction of rat primary hepatocyte.

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The SH3 Domain of Phospholipase C-${\gamma}1$ Associates with Shc

  • Kim, Myung-Jong;Hwang, Jong-Ik;Chang, Jong-Soo;Ryu, Sung-Ho;Suh, Pann-Ghill
    • BMB Reports
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    • v.32 no.2
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    • pp.119-126
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    • 1999
  • The SH3 domain of PLC-${\gamma}1$ has been known to induce DNA synthesis. However, little is known about the putative effector proteins that associate with the domain. In this report, we provide evidence that the SH3 domain of PLC-${\gamma}1$ associates with Shc, which has been implicated in the activation of p21Ras in response to many growth factors. The association between Shc and PLC-${\gamma}1$ is enhanced either by v-Src-induced transformation or EGF-stimulation in vivo and in vitro. Furthermore, from transient expression studies with COS-7 cells, we show that the SH3 domain of PLC-${\gamma}1$ is required for association with Shc in vivo, whereas tyrosyl phosphorylation of PLC-${\gamma}1$ is not. Taken together, we suggest that Shc might be involved in the PLC-${\gamma}1$-mediated signaling pathway.

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