Retinoic acid downregulates Rae1 leading to APCCdh1 activation and neuroblastoma SH-SY5Y differentiation

Regulation of APC/CCdh1ubiquitin ligase in differentiation of human embryonic stem cells

“…8,11 It has been reported that levels of Rae1 declined in neuroblastoma cells differentiated by treatment with retinoic acid. 6 However, we could not detect any change in levels of Rae1 in differentiating human embryonic cells (Fig. 2C).…”

“…6 This could explain increased activity of APC/C, which is localized mainly in the nucleus in non-mitotic cells. However, in human embryonic stem cells we observed that most Cdh1 is located mainly in the nucleus even in the undifferentiated state, and we could not detect changes in nuclear/cytoplasmic distribution in the course of differentiation (Fig.…”

Retinoic acid signaling and neuronal differentiation

“…An important downstream target of E47 is the CIK p57 Kip2 ; hence, Id2 effectively down-regulates p57 Kip2 via E47 inhibition, thus promoting proliferation in neuroblastoma cells [156]. Activation of the anaphase promoting complex with Cdh1 coactivator (APC Cdh1 ) by differentiation signals (such as RA [158]) causes Id2 to be targeted for degradation, thus promoting neuronal differentiation [159]. When Cdh1 is ablated in mice, increased proliferation in neurospheres and stabilization of substrates such as Geminin is observed [160].…”

A decade of the anaphase-promoting complex in the nervous system

“…Correspondingly, the ventricular and subventricular zones in conditional Cdh1 knockout mice contain a higher proportion of precursor cells and fewer post-mitotic neurons (Delgado-Esteban et al 2013), suggesting that Cdh1 promotes neuronal differentiation in the cerebral cortex. Cdh1-APC regulates neuronal differentiation through rapid degradation of the protein Skp2, leading to the stabilization of the Cdk inhibitor p27 (Carrano et al 1999;Cuende et al 2008), which in turn is thought to promote neuronal differentiation of cortical progenitor cells (Cuende et al 2008;Harmey et al 2009;Delgado-Esteban et al 2013). The phosphorylation status of Cdh1 is critical in regulating Cdh1-APC function in neuronal differentiation.…”