Skip to main content

The ASB2 gene

Identification of the ASB2 gene

All-trans retinoic acid 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). Indeed, transcripts of the ASB2α isoform of ASB2 were identified as expressed in retinoic acid-treated acute promyelocytic leukemia (APL) cells. We also demonstrated that ASB2 is repressed by the oncogenic PML-RARα protein in APL cells. This has been confirmed by others and extended to other fusion proteins (PLZF-RARα and AML1-ETO) that act as transcriptional repressors, suggesting that ASB2 repression in human Acute Myeloid Leukemia (AML) may participate in the transformation process. Furthermore, a recent study demonstrated that the oncogenic effects of the FTO demethylase in AML are mediated through the regulation of ASB2 transcript stability.

 

One gene, two transcripts and two protein isoforms in humans and mice

The mouse and the human ASB2 genes encode two transcripts that are translated into the α and β protein isoforms that differ in their N-terminal regions (Heuzé et al., 2005; Bello et al., 2009; Lamsoul et al., 2013; Métais et al., 2018). Of note, the Danio rerio homologue of the human and mouse ASB2α proteins is encoded by the Asb2b gene located on chromosome 17 while the homologue of the human and mouse ASB2β proteins is encoded by the Asb2a gene located on chromosome 20 (Métais et al., 2018).

 

ASB2 is an essential gene, critical to heart morphogenesis and function

We demonstrated that the complete loss of the ASB2 gene in mice results in embryonic lethality around E9.5, demonstrating no functional redundancy between ASB proteins during embryogenesis (Métais et al., 2018). In fact, ASB2α transcripts are mainly expressed in the heart of wild-type embryos at E9.5 while ASB2β transcripts are expressed from E11.5 onward in the heart of embryos and are the main ASB2 transcripts expressed in the heart of adult mice. We showed that ASB2-/- embryos die in utero from heart beat defects although the overall patterning and the cardiac differentiation program had occurred. Importantly, our results are in agreement with results from others showing that Asb2b zebrafish mutants exhibit pericardial oedema and display reduced cardiac functions. Taken together, these indicate that ASB2α plays an essential role in heart development from fish to mice.

Read the press release (in french)

 

Combined Stacks time 20fps.gif

Movies of living ASB2+/+ and ASB2-/- mouse embryos at 9 s.p.