Oncogene
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Comparative Study
Selective pyrrolo-pyrimidine inhibitors reveal a necessary role for Src family kinases in Bcr-Abl signal transduction and oncogenesis.
Chronic myelogenous leukemia (CML) is defined by the presence of the Philadelphia (Ph) chromosome, which results in the expression of the 210 kDa Bcr-Abl tyrosine kinase. Bcr-Abl constitutively activates several signaling proteins important for the proliferation and survival of myeloid progenitors, including the Src family kinases Hck and Lyn, the Stat5 transcription factor and upstream components of the Ras/Erk pathway. Recently, we found that kinase-defective Hck blocks Bcr-Abl-induced transformation of DAGM myeloid leukemia cells to cytokine independence, suggesting that activation of the Src kinase family may be essential to oncogenic signaling by Bcr-Abl. ⋯ Both inhibitors blocked Stat5 and Erk activation, consistent with the suppressive effects of the compounds on survival and proliferation. In contrast, the phosphotyrosine content of Bcr-Abl and its endogenous substrate CrkL was unchanged at inhibitor concentrations that induced apoptosis, blocked oncogenic signaling and inhibited Src kinases. These data implicate the Src kinase family in Stat5 and Erk activation downstream of Bcr-Abl, and identify myeloid-specific Src kinases as potential drug targets in CML.
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Despite extensive effort in improvement of diagnosis and treatment of patients with lung cancer in past three decades, the overall survival of patients with the disease remains dismal. Because the development of lung cancer takes a few decades, early diagnosis of the disease or identification of truly high-risk populations may provide us opportunity to successfully cure or prevent the disease. ⋯ Along with identification of molecular abnormalities in the early lung tumorigenesis, advanced molecular analytic technologies have been emerged, which may facilitate development of rapid and effective methods for early diagnosis and risk assessment. Here, I discuss recent progresses in understanding of early molecular abnormalities in lung cancer, efforts of translating laboratory findings to clinical tests, and prospective of biomarkers in lung cancer diagnosis and risk assessment.
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Retinal pigmented epithelial (RPE) cell integrity is critical to the maintenance of retina functions and RPE cells do not proliferate in adults. The activation of RPE results in cell proliferation which may be associated with proliferative retinopathy and choroidal melanoma. Mitogen-activated protein kinase (MAPK) is believed to be a key participant in the response to mitogenic stimuli. ⋯ Moreover, inhibition of the cAMP-activated small G protein Rap1, partially reversed the inhibitory effects of cAMP on cell proliferation and MEK/ERK activation. The requirement for Ras and ERK1/2, the lack of ERK1/2 regulation by PKA and the cAMP/Rap1 counter-regulatory pathway for ERK-mediated cell proliferation suggest complex regulation of signalling in RPE cells. These data may have important implications for the development of more selective models for retinal anti-proliferative therapies.
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BCR/ABL fusion tyrosine kinase is responsible for the initiation and maintenance of the Philadelphia chromosome (Ph(1))-positive chronic myelogenous leukemia (CML) and a cohort of acute lymphocytic leukemias (ALL). STI571 (Gleevec), a novel anti-leukemia drug targeting BCR/ABL kinase can induce remissions of the Ph(1)-positive leukemias. STI571 was recently combined with the standard cytostatic drugs to achieve better therapeutic results and to overcome emerging drug resistance mechanisms. ⋯ Single colony RT-PCR assay showed that colonies arising from the mixture of CML cells and normal bone marrow cells after treatment with STI571+WT were selectively depleted of BCR/ABL-positive cells. Biochemical analysis of the CML cells after the treatment revealed that combination of STI571+WT caused a more pronounced activation of caspase-3 and induced massive apoptosis, in comparison to STI571 and WT alone. In conclusion, combination of STI571+WT or STI571+LY may represent a novel approach against the Ph(1)-positive leukemias.