CSE1L/CAS: its role in proliferation and apoptosis.
CAS/CSE1L is the human homologue of the yeast gene CSE1. It was first cloned while searching for genes that rendered breast cancer cells resistant towards toxin induced apoptosis. Since depletion of CSE1 leads to cell-cycle arrest, CAS is thought to be involved in proliferation. CAS functions in the mitotic spindle checkpoint. CAS is located on chromosome 20q13, a locus often amplified in cancers of various origin, e.g. colonic or breast cancer. Since genetic instability is a hallmark of cancer, amplification or over expression of the CAS gene might interfere with or override its role in the mitotic spindle checkpoint. CAS is also implicated in the nuclear to cytoplasmic reshuffling of importin alpha, which itself is necessary for the nuclear transport of several proliferation activating proteins, transcription factors, oncogene and tumor suppressor gene products such as p53 and BRCA1. Inhibition of MEK1 mediated phosphorylation has been shown to enhance paclitaxel (Taxol) induced apoptosis in breast, ovarian, and lung tumor cell lines in-vitro. Since CAS is also phosphorylated (activated) by MEK1, and since the anti-cancer drug Taxol alters the microtubule assembly and activates pro-apoptotic signaling pathways, altering the activity/phosphorylation status of CAS via MEK1 inhibition may present a potential strategy in experimental cancer therapy.
Behrens
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Institute of Pathology, University of Bonn, Bonn, Germany.
Brinkmann
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Wellmann
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D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D029563:Cellular Apoptosis Susceptibility Protein / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism; D017239:Paclitaxel / Q000627:therapeutic use; D010766:Phosphorylation; D014407:Tumor Cells, Cultured; D028901:alpha Karyopherins / Q000378:metabolism
D029563:Cellular Apoptosis Susceptibility Protein; D028901:alpha Karyopherins; D017239:Paclitaxel