Expression of the CDH1-associated form of the anaphase-promoting complex in postmitotic neurons

Abstract

The anaphase-promoting complex͞cyclo-some (APC) is a tightly cell cycle-regulated ubiquitin-protein ligase that targets cyclin B and other destruction boxcontaining proteins for proteolysis at the end of mitosis and in G1. Recent work has shown that activation of the APC in mitosis depends on CDC20, whereas APC is maintained active in G1 via association with the CDC20-related protein CDH1. Here we show that the mitotic activator CDC20 is the only component of the APC ubiquitination pathway whose expression is restricted to proliferating cells, whereas the APC and CDH1 are also expressed in several mammalian tissues that predominantly contain differentiated cells, such as adult brain. Immunocytochemical analyses of cultured rat hippocampal neurons and of mouse and human brain sections indicate that the APC and CDH1 are ubiquitously expressed in the nuclei of postmitotic terminally differentiated neurons. The APC purified from brain contains all core subunits known from proliferating cells and is tightly associated with CDH1. Purified brain APC CDH1 has a high cyclin B ubiquitination activity that depends less on the destruction box than on the activity of mitotic APC CDC20 . On the basis of these results, we propose that the functions of APC CDH1 are not restricted to controlling cell-cycle progression but may include the ubiquitination of yet unidentified substrates in differentiated cells.

Loss of the anaphase-promoting complex in quiescent cells causes unscheduled hepatocyte proliferation

“…In addition to its key regulatory function during cell proliferation, the APC/C is known to be also active in postmitotic differentiated cells (Gieffers et al 1999). However, the significance of this activity is not understood.…”

“…Most if not all APC/C subunits as well as Cdh1-like proteins are found in tissues composed of fully differentiated cells (Gieffers et al 1999). Indeed, a fully active complex can be isolated from adult mouse brain tissues.…”

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

“…Indeed, our results shown in Figures 2d and e confirm this notion in our cell model, since expression of Skp2Ddb mutant, refractory to Cdh1-mediated targeting, but not wild-type Skp2, prevented RA-induced p27 stabilization and cell cycle arrest in neuroblastoma cells. Previous data have reported that the APC activator Cdh1, but not Cdc20, is accumulated in postmitotic neurons (Gieffers et al, 1999;Almeida et al, 2005). Here, we directly assessed the possible involvement of APC Cdh1 in RA-induced SH-SY5Y cell differentiation.…”

Mouse ribonucleotide reductase R2 protein: A new target for anaphase-promoting complex-Cdh1-mediated proteolysis

“…20). Cdh1-APC recognizes either a destruction box or a newly discovered recognition signal, the KEN box, and it is active in late mitosis and during G 1 ͞G o (19,21,22). In S phase, cell cycle-dependent phosphorylation of Cdh1 causes it to dissociate from the APC, which is then kept inactive during S phase and G 2 until the following mitosis (23).…”