Abstract
Hox proteins are conserved homeodomain transcription factors known to be crucial regulators of animal development. As transcription factors, the functions and modes of action (co-factors, target genes) of Hox proteins have been very well studied in a multitude of animal models. However, a handful of reports established that Hox proteins may display molecular activities distinct from gene transcription regulation. Here, we reveal that Hoxa2 interacts with 20S proteasome subunits and RCHY1 (also known as PIRH2), an E3 ubiquitin ligase that targets p53 for degradation. We further show that Hoxa2 promotes proteasome-dependent degradation of RCHY1 in an ubiquitin-independent manner. Correlatively, Hoxa2 alters the RCHY1-mediated ubiquitination of p53 and promotes p53 stabilization. Together, our data establish that Hoxa2 can regulate the proteasomal degradation of RCHY1 and stabilization of p53.
Highlights
Hoxa2 belongs to the mammalian Hox genes family that encodes 39 highly conserved homeodomain transcription factors mainly involved in embryonic development and in a large number of pathological processes [1,2,3,4]
While verifying that the fusion proteins were properly expressed in transfected cells, we were surprised to observe that, compared to cells transfected with the glutathione S-transferase (GST)-RCHY1 vector alone, cells co-transfected with FLAGHoxa2 expression vector showed barely detectable weak GSTRCHY1 protein levels
Since the GST-RCHY1 expression construct was based on a constitutively active CMV promoter, we hypothesized that the influence of Hoxa2 on the RCHY1 protein level was most likely due to an impact on RCHY1 protein stability
Summary
Hoxa belongs to the mammalian Hox genes family that encodes 39 highly conserved homeodomain transcription factors mainly involved in embryonic development and in a large number of pathological processes [1,2,3,4]. Hox transcriptional targets were functionally identified through transcriptomic screenings [16,17] and chromatin immunoprecipitation assays [18,19,20,21] In parallel to their transcriptional activity, some Hox proteins have been involved in non-transcriptional processes. HOXD13, for example, binds DNA replication origins, primarily during G1 phase of the cell cycle, promotes the assembly of pre-replication complexes and induces DNA synthesis [27]. Such a role in cell cycle has been suggested for HOXC10 [28] or Hoxb, which has been associated with hematopoietic cell proliferation [29]. Hoxb takes part in an E3 ubiquitin ligase complex that recognizes Geminin, an anti-replicative protein, and induces its degradation [30]
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