Wild-type H- and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response.

Mutations in KRAS are prevalent in human cancers and universally predictive of resistance to anticancer therapeutics. Although it is widely accepted that acquisition of an activating mutation endows RAS genes with functional autonomy, recent studies suggest that the wild-type forms of Ras may contribute to mutant Ras-driven tumorigenesis. Here, we show that downregulation of wild-type H-Ras or N-Ras in mutant K-Ras cancer cells leads to hyperactivation of the Erk/p90RSK and PI3K/Akt pathways and, consequently, the phosphorylation of Chk1 at an inhibitory site, Ser 280.

A postmarketing surveillance study on erbitux (cetuximab) in patients with metastatic colorectal cancer refractory to irinotecan-containing treatment.

Objective: This postmarketing surveillance study evaluated the safety and efficacy of cetuximab therapy in patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC) in Taiwan.

Methods: Patients with EGFR-expressing mCRC who had failed prior irinotecan-based chemotherapy and were receiving cetuximab therapy were monitored for treatment efficacy and safety from the time of first infusion until 28 days after the last infusion regardless of the reasons fordiscontinuation. The study followed 269 patients for approximately 2 years.

Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis.

Mammalian cells contain three closely related ras genes, H-ras, K-ras and N-ras. Although in a given tumour type, oncogenic mutations are selectively observed in only one of the ras genes, the acquisition of the transformed phenotype has been shown to require the contribution of the normal products of the other ras genes. Here we demonstrate that oncogenic K-Ras promotes the activation of wild-type H- and N-Ras.

Perturbation of cytoskeleton dynamics by the opposing effects of Rac1 and Rac1b.

Rac1, a ubiquitously expressed member of the Rho GTPase family, plays a pivotal role in the regulation of multiple cellular processes including cytoskeleton reorganization, cell growth, differentiation and motility. Here we show that the tumor-specific splice variant of Rac1, Rac1b, negatively regulates Rac1 activity. The expression of Rac1b in HeLa cells interferes with Rac1 activation by PDGF, leads to a reduction in membrane-bound Rac1 and promotes an increase in Rho activity.

DNA methyltransferase 1 expression and promoter methylation of E-cadherin in mucoepidermoid carcinoma.

Background: Loss of E-cadherin expression is found frequently in many types of human malignancies, including mucoepidermoid carcinoma (MEC). CpG methylation in the promoter region has proven important in the regulation of gene expression implicated in malignant transformation. DNA methyltransferases (DNMTs) are the major enzymes involved in establishing genomic methylation patterns.

Phosphorylation by glycogen synthase kinase of inhibitor-2 does not change its structure in free state.

Inhibitor-2 (I2) is a thermostable protein that specifically binds to the catalytic subunit of protein phosphatase-1 (PP1), resulting in the formation of the inactive holoenzyme, ATP-Mg-dependent phosphatase. Phosphorylation of I2 at Thr-72 by glycogen synthase kinase-3 (GSK-3) results in activation of the phosphatase, suggesting that kinase action triggers conformational change in the complex. In this paper, we characterize the effect of GSK-3 phosphorylation on the structure of free state I2[1-172] by nuclear magnetic resonance and circular dichroism spectroscopy, and show that phosphorylation has no significant effect on its conformation.

Identification of the alternative splice products encoded by the human protein phosphatase inhibitor-1 gene.

We have isolated three major cDNA fragments of protein phosphatase inhibitor-1 from human brain and liver by RT-PCR. The 536 bp fragment encoded the wild-type of inhibitor-1 while two other fragments were alternative splice products of the inhibitor-1 gene, which was confirmed by partial genomic DNA sequencing. The 380 bp fragment encoded an in-frame 51-residue-deleted inhibitor-1, named inhibitor-1alpha, and the deletion occurred from residue 84 to 134 of inhibitor-1.