Expression data from discodermolide sensitive and resistant cell lines
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Susan Chao
PROVIDER: E-GEOD-25904 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Discodermolide treatment of A549 results in senescence. We compared cells resistant to disco-induced senescence to those that are sensitive to senescence induction. We also examined the gene expression of resistant (AD32) cells overexpressing 4E-BP1, a protein known to restore sensitivity to discodermolide in these cells.
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Project description:B7x (B7-H4 or B7S1) is the seventh member of the B7 family and the in vivo function remains largely unknown. Despite new genetic data linking the B7x gene with autoimmune diseases, how exactly it contributes to peripheral tolerance and autoimmunity is unclear. Here we showed that B7x protein was not detected on antigen-presenting cells or T cells in both human and mice, which is unique in the B7 family. As B7x protein is expressed in some peripheral cells such as pancreatic b cells, we utilized a CD8 T cell-mediated diabetes model (AI4ab) in which CD8 T cells recognize an endogenous self-antigen, and found that mice lacking B7x developed more severe diabetes than control AI4ab mice. Conversely, mice overexpressing B7x in the b cells (Rip-B7xAI4ab) were diabetes free. Furthermore, adoptive transfer of effector AI4ab CD8 T cells induced diabetes in control mice, but not in Rip-B7xAI4ab mice. Mechanistic studies revealed that pathogenic effector CD8 T cells were capable of migrating to the pancreas but failed to robustly destroy tissue when encountering local B7x in Rip-B7xAI4ab mice. Although AI4ab CD8 T cells in Rip-B7xAI4ab mice and AI4ab mice showed similar cytotoxic function, cell death, and global gene expression profiles, these cells had greater proliferation in AI4ab mice than in RIP-B7xAI4ab mice. These results suggest that B7x in nonlymphoid organs prevents peripheral autoimmunity partially through inhibiting proliferation of tissue-specific CD8 T cells and that local overexpression of B7x on pancreatic b cells is sufficient to abolish CD8 T cell-induced diabetes. AI4 mice developed T1D and Rip-B7x AI4 mice were resistant to T1D. Total RNA was collected and gene expression compared between AI4 CD8 T cells from AI4 and Rip-B7xAI4 mice.
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Project description:Cyclin-dependent kinases 13 (CDK13) has been suggested to phosphorylate RNA polymerase II and is involved in transcriptional activation. However, whether CDK13 catalyzes other protein substrates and how CDK13 contributes to tumorigenesis remain largely unclear. Herein, we identify key translation machinery components 4E-BP1 and eIF4B as novel CDK13 substrates. CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422 such that genetic or pharmacological inhibition of CDK13 perturbs RNA translation. Polysome profiling analysis shows that MYC oncoprotein synthesis depends on the CDK13-regulated translation in colorectal cancer (CRC), and CDK13 is required for CRC cell proliferation. As mTORC1 has been shown to phosphorylate the 4E-BP1 and eIF4B, knockdown or inhibition of CDK13 in combination with mTORC1 inhibitor rapamycin further dephosphorylates 4E-BP1 and eIF4B and blocks protein synthesis. As a result, dual inhibition of CDK13 and mTORC1 accelerated CRC cell death and again MYC were significantly downregulated upon combination treatment. These findings demonstrate a pro-tumorigenic role of CDK13 in CRC and shed light on the role of CDK13 in protein synthesis by direct phosphorylation of translation initiation factors. Therefore, therapeutic targeting of CDK13 alone or in combination with rapamycin may pave a new way for CRC treatment.
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