• Bulletin of the Korean Chemical Society
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• v.26 no.2
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• pp.327-330
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• 2005

• BMB Reports
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• v.33 no.5
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• pp.391-395
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• 2000

Calexcitin, a calcium-binding protein, was previously cloned and functionally characterized in the squid Loligo pealei. We now report the cloning of a second form of Calexcitin, Calexcitin-2, found in the squid Todarodes pacificus optic lobe. Calexcitin-2 has a significantly different carboxyl terminal region than Calexcitin-1. It lacks the CAAX motif, which is a farnesylation site. The amino acid sequence of Calexcitin-2 shows an 84% identity with Calexcitin-1 and also displays a strong cross immunoreactivity. Western blotting shows that Calexcitin-2 was expressed exclusively in the optic lobe region of squid, but not in other body organs. Regardless of its lack of conserved regions for GTP-binding, Calexcitin-2 shows moderately low affinity GTP-binding and also shows dramatic conformational change induced by GTP-binding. Three possible GTP-binding region mutations, K142A, D144A, and K157A, did not change the G TP binding affinity. This raises the possibility that Calexcitin-2 may have a novel GTP-binding motif.

• Archives of Pharmacal Research
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• v.25 no.6
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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.

• Journal of Life Science
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• v.20 no.2
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• pp.202-207
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• 2010

Ras genes are responsible for up to 30% of human tumor mutations and are composed of three isoforms: H-Ras, K-Ras and N-Ras. The post-translational modification of the CAAX motif of the Ras protein is essential in Ras actions. In the present study, we studied the effects of novel farnesyl transferase inhibitors (FTIs), YH3938 and YH3945, on the actions of oncogenic mutants of H-Ras, K-Ras and N-Ras. YH3938 and YH3945 completely reverted the proliferation and morphology of oncogenic H-Ras-transformed Rat2 cells, but not of oncogenic K-Ras-transformed Rat2 cells. Oncogenic N-Ras-transformed Rat2 cells were slightly affected. Activation of SRE promoters by oncogenic H-Ras and N-Ras, but not by K-Ras, were inhibited by treatment with YH3938 and YH3945. Using bandshift analysis, YH3938 suppressed the processing of oncogenic H-Ras and N-Ras, but not that of oncogenic K-Ras protein. YH3945 only inhibited the processing of H-Ras. From these results, we conclude that YH3938 and YH3945 specifically inhibit actions of oncogenic H-Ras through inhibition of its farnesylation, that YH3938 also inhibits N-Ras activity in a dose-dependent manner, and that these drugs have no effect on oncogenic K-Ras activity.

• Animal cells and systems
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• v.13 no.4
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• pp.399-403
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• 2009

$p19^{ras}$ is an alternative splicing variant of the proto-oncogene c-H-ras pre-mRNA of $p21^{ras}$. In contrast to $p21^{ras}$, $p19^{ras}$ does not have a C-terminal CAAX motif that targets the plasma membrane and is localized to both the cytoplasm and nucleus. We found that $p19^{ras}$ activated the transcriptional activity of $p73{\beta}$ through protein-protein interactions in the nucleus. p73 is known to play an important role in cellular damage responses such as apoptosis. Although p73 is a structural and functional homologue of p53, p73-mediated apoptosis has not yet been clearly elucidated. In this study, we demonstrate that the interaction between $p19^{ras}$ and $p73{\beta}$ accelerated $p73{\beta}$-induced apoptosis through a caspase-3 dependent pathway. Treatment with DEVD-CHO, a caspase inhibitor, also strengthened $p73{\beta}$-mediated apoptosis through a caspase-3 dependent pathway. Furthermore, the enhanced transcriptional activity of endogenous $p73{\beta}$ by treatment with Taxol was amplified by $p19^{ras}$ overexpression, which markedly increased caspase-3 dependent apoptosis in the p53-null SAOS2 cancer cell line. Our findings indicate a functional linkage between $p19^{ras}$ and p73 in caspase-3 mediated apoptosis of cancer cells.