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Transcription Factor in Glioma Cells Regulated by Novel Genes

Scientists discovered a cellular pathway in the deadly brain cancer malignant glioma, a pathway essential to the cancer's ability to grow--and a potential target for therapy that would stop the cancer's ability to thrive.

A genome-wide RNAi screening tool was used to identify a dozen genes that affect the function of a crucial protein necessary for glioma cells to grow. In addition, the key pathway appears in laboratory cultures and mouse models to be susceptible to two cancer drugs already in use for other types of cancer. A hallmark of cancer is uncontrolled cell growth, often caused by over-expression of genes that help cells survive, or under-expression of those genes that induce normal cell death. Genes that are expressed highly in cancer cells and are essential for their survival are attractive targets for drug therapy.

Recent research revealed the essential cellular survival pathway, CREB3L2-ATF5-MCL1, in malignant glioma. The team identified novel genes that regulate the expression of a transcription factor called ATF5 (activating transcription factor 5) in malignant glioma cells.

ATF5 is linked to many cellular function including cell cycle progression, metabolite homeostasis cellular differentiation and apoptosis. ATF5 is a member of basic-region leucine zipper (bZIP) proteins family which binds the cAMP response element (CRE) consensus sequence: 5'GTGACGT(C/A)(G/A). This sequence is present in many viral and cellular promoters. ATF within or between subgroups can form homo- or hetero-dimer through the bZIP domain and the dimer can then bind to the DNA through the basic-motif and function as a transcription factor. Recently, another novel ATF5 consensus DNA binding sequence (CYTCTYCCTTW) was found in C6 glioma and MCF7 using a cyclic amplification and selection of targets. The discovery of at least one previously unknown genetic pathway that appears to regulate this key transcription factor, and the subsequent determination that the cancer drugs sorafenib and temozolomide inhibit glioma growth, indicate new possibilities for potential therapeutics.