Interaction of the pRB-family proteins with factors containing paired-like homeodomains

Abstract

The speci®c loss of pRB or p107 together with p130 disrupts the normal development of only a very limited spectrum of tissues. These developmental defects have been attributed primarily to deregulation of E2F activity and consequent uncontrolled proliferation. We hypothesized, however, that the tissue-speci®c nature of these defects may also re¯ect deregulation of pRB-family associated factors that are speci®cally involved in determining cell fate. We report here that the pRBfamily members interact with transcription factors which contain paired-like homeodomains such as MHox, Chx10 and Pax-3. The interaction between the pRBfamily and the paired-like homeodomain proteins was initially identi®ed in a yeast two-hybrid screen where the N-terminal portion of p130 was used to isolate interacting factors from an embryonic mouse library. This interaction was con®rmed by in vitro binding and co-immunoprecipitation assays. We show further that coexpression of Pax-3 dependent pRB, p107 or p130 with Pax-3 causes repression of activated transcription from the c-met promoter. These data demonstrate that the pRB-family proteins can modulate the activity of factors which speci®cally control cell fate and/or dierentiation as well as controlling cell cycle regulators.

Retinoblastoma protein acts as Pax 8 transcriptional coactivator

“…This hypothesis is also supported by studies that show a direct interaction between pRb and factors containing paired-like homeodomains (Wiggan et al, 1998). Interestingly, Eberhard and Busslinger (1999) have demonstrated the direct interaction between Pax 5 and pRb both in vitro and in vivo and it has been reported that pRb interacts with Pax 2 (Yuan et al, 2002).…”

Cell-type-specific regulation of distinct sets of gene targets by Pax3 and Pax3/FKHR

“…For example, since pRB represses the activity of Pax3 (Wiggan et al, 1998), we predicted that Pax3-dependent induction of a MET in the pRB-positive human osteosarcoma, U2-OS, would be retarded. As Figure 4a and b illustrates, a small but significant reduction in the size of U2-OS cells occurs following expression of Pax3.…”

“…Pax3 activity is further regulated through binding of other nuclear factors. For example, both Daxx and pRB (Wiggan et al, 1998) associate with Pax3, repressing Pax3-dependent transcription in a dose-dependent manner.…”

Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR

“…Hence, the activity of the fusion protein is strongly in¯uenced by cell background, either due to lack of an appropriate coactivator in ®broblasts or lack of a repressing activity in myoblasts. Interestingly, two proteins have recently been identi®ed that can repress the activity of Pax3 but not PAX3/FKHR through direct interaction with the paired-type homeodomain, namely pRb and hDaxx Wiggan et al, 1998).…”