Tumor suppressor protein C53 antagonizes checkpoint kinases to promote cyclin-dependent kinase 1 activation

Abstract

Cyclin-dependent kinase 1 (Cdk1)/cyclin B1 complex is the driving force for mitotic entry, and its activation is tightly regulated by the G2/M checkpoint. We originally reported that a novel protein C53 (also known as Cdk5rap3 and LZAP) potentiates DNA damage-induced cell death by modulating the G2/M checkpoint. More recently, Wang et al. (2007) found that C53/LZAP may function as a tumor suppressor by way of inhibiting NF-κB signaling. We report here the identification of C53 protein as a novel regulator of Cdk1 activation. We found that knockdown of C53 protein causes delayed Cdk1 activation and mitotic entry. During DNA damage response, activation of checkpoint kinase 1 and 2 (Chk1 and Chk2) is partially inhibited by C53 overexpression. Intriguingly, we found that C53 interacts with Chk1 and antagonizes its function. Moreover, a portion of C53 protein is localized at the centrosome, and centrosome-targeting C53 potently promotes local Cdk1 activation. Taken together, our results strongly suggest that C53 is a novel negative regulator of checkpoint response. By counteracting Chk1, C53 promotes Cdk1 activation and mitotic entry in both unperturbed cell-cycle progression and DNA damage response.

Neural stem cell- and neurogenesis-related gene expression profiles in the young and aged dentate gyrus

“…This gene expression pattern is consistent with the earlier observation that neuronal fate-choice decision of newly born cells in the DG is unaltered with aging (Rao et al , 2006. Furthermore, Cdk5rap3 is involved in modulating the G2/M DNA damage checkpoint and can associate with and regulate the Cdk1-cyclin B1 complex, which is the driving force for mitotic entry (Jiang et al 2009). Studies suggest that Cdk5rap3 promotes Cdk1 activation and mitotic entry in both unperturbed cell cycle progression and DNA damage response (Jiang et al 2009).…”

“…Furthermore, Cdk5rap3 is involved in modulating the G2/M DNA damage checkpoint and can associate with and regulate the Cdk1-cyclin B1 complex, which is the driving force for mitotic entry (Jiang et al 2009). Studies suggest that Cdk5rap3 promotes Cdk1 activation and mitotic entry in both unperturbed cell cycle progression and DNA damage response (Jiang et al 2009). In this context, increased expression of Cdk5rap3 in the aged DG may be to counteract the senescent changes (such as increased quiescence) that are believed to occur in NSCs of the aged DG (Hattiangady and Shetty 2008;Encinas et al 2011).…”

Caspase-mediated cleavage of C53/LZAP protein causes abnormal microtubule bundling and rupture of the nuclear envelope

“…Genetic study in zebrafish demonstrates that C53/LZAP is essential for normal animal development [8]. Our previous studies have demonstrated its involvement in modulating cell cycle checkpoint by negatively regulating checkpoint kinases [6,7]. Moreover, it plays an important role in tumorigenesis and metastasis.…”

“…In correlation with its potential diverse functions, C53/LZAP was found in multi-subcellular compartments, including cytosol, nucleus, nucleolus and centrosomes [5,7,12,13]. Not surprisingly, it was reported to interact with a wide range of proteins, including p35 [3], Rel A [5], Chk1/2 [7], PAK4 [9], ARF [4], p38 MAPK [14], Ufl1 (also known as RCAD, NLBP and Maxer) [12,[15][16][17] and γ-tubulin [13]. Yet the underlying biochemical nature of these protein-protein interactions remains largely unclear.…”

“…Recent studies suggest that it functions in various signaling pathways, ranging from transcriptional regulation to cell cycle progression [5][6][7]. Genetic study in zebrafish demonstrates that C53/LZAP is essential for normal animal development [8].…”