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ASB2 alpha

All-trans retinoic acid (RA) induces differentiation of acute promyelocytic leukemia (APL) cells, this serves as an effective therapy and provides an opportunity to investigate the differentiation process. Using a subtraction cloning strategy to isolate genes upregulated during this process, we have identified and characterized three novel genes: JAML (Junctional Adhesion Molecule -Like) (Moog-Lutz et al., 2003; Luissint et al., 2008);PRAM-1 (PML-RARα target gene encoding an Adapter Molecule 1) (Moog-Lutz et al., 2001, Denis et al., 2005); and ASB2 (Ankyrin repeat-containing protein with a Suppressor of Cytokine signaling Box 2) (Guibal et al., 2002).

Although ASB2 was initially identified as induced by retinoic acid in APL cells, it is specifically expressed in normal immature hematopoietic cells and so is likely to be relevant during early hematopoiesis. FurthermoreASB2 is a transcriptional target of the PML-RARα oncoprotein suggesting that ASB2 repression may participate in the transformation process. ASB2 encodes two isoforms ASB2α and ASB2β that are involved in hematopoietic and myogenic differentiation, respectively. Retinoic acid induces expression of ASB2α in APL cells and ASB2α expression inhibits growth and promotes commitment of myeloid leukemia cells, recapitulating an early step critical for differentiation. ASB2α is the specificity subunit of an active Cullin 5-RING (CRL) -type E3 ubiquitin ligase complex, suggesting that ASB2α might function in hematopoiesis by targeting specific proteins involved in blocking differentiation to destruction by the proteasome machinery. We have showed that ASB2α ubiquitin ligase activity drives proteasome-mediated degradation of the actin-binding protein Filamins (Filamin A, Filamin B and Filamin C) and can regulate integrin-dependent functions such as cell spreading and cell migration (Heuze et al., 2008; Burande et al.,2009; Baldassarre et al., 2009). Because integrins which bind directly to Filamins, play a major role in anchoring hematopoietic stem cells to the hematopoietic niche during development and following transplantation in mice, it is tempting to speculate that by targeting Filamins to proteasomal degradation, ASB2α may modulate hematopoietic stem cell fate within the hematopoietic niche.


The overall objective of our project is to further improve our understanding of the molecular mechanisms controlling the targeting of proteins for proteasomal degradation. Our specific aims are :

  • to determine ASB2α function in hematopoiesis and to investigate the role of ASB2α deregulation in leukemogenesis

        1 - Inhibition of ASB2α function during in vitro differentiation of normal and leukemia hematopoietic cells;

        2 - Targeted disruption of mouse ASB2 using a conditional gene inactivation strategy.

  • to decipher ASB2α mechanisms of action through the identification and characterization of ASB2α substrates
           1 - Identification and characterization of ASB2α partners and substrates;

       2 - Relevance of ASB2α substrate degradation in physiological and physiopathological contexts.


Contact : Pierre Lutz