Human Gene Set: PODAR_RESPONSE_TO_ADAPHOSTIN_DN


Standard name PODAR_RESPONSE_TO_ADAPHOSTIN_DN
Systematic name M8876
Brief description Down-regulated genes in MM1.S cells (multiple myeloma) treated with adaphostin [PubChem=387042], a tyrosine kinase inhibitor with anticancer properties.
Full description or abstract Here we show the antimyeloma cytotoxicity of adaphostin and carried out expression profiling of adaphostin-treated multiple myeloma (MM) cells to identify its molecular targets. Surprisingly, c-Jun was the most up-regulated gene even at the earliest point of analysis (2 h). We also observed adaphostin-induced c-Abl cleavage in immunoblot analysis. Proteasome inhibitor bortezomib, but not melphalan or dexamethasone, induced similar effects, indicating unique agent-dependent mechanisms. Using caspase inhibitors, as well as caspase-resistant mutants of c-Abl (TM-c-Abl and D565A-Abl), we then showed that c-Abl cleavage in MM cells requires caspase activity. Importantly, both overexpression of the c-Abl fragment or c-Jun and knockdown of c-Abl and c-Jun expression by small interfering RNA confirmed that adaphostin-induced c-Jun up-regulation triggers downstream caspase-mediated c-Abl cleavage, inhibition of MM cell growth, and induction of apoptosis. Finally, our data suggest that this mechanism may not only be restricted to MM but may also be important in a broad range of malignancies including erythroleukemia and solid tumors.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 17308109   Authors: Podar K,Raab MS,Tonon G,Sattler M,Barilà D,Zhang J,Tai YT,Yasui H,Raje N,DePinho RA,Hideshima T,Chauhan D,Anderson KC
Exact source Table 1S
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Source species Homo sapiens
Contributed by Jessica Robertson (MSigDB Team)
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identifier namespace		 AFFY_HG_U133
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Version history 3.0: First introduced

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