CDCA4 Is an E2F Transcription Factor Family-induced Nuclear Factor That Regulates E2F-dependent Transcriptional Activation and Cell Proliferation

Abstract

The TRIP-Br1/p34 SEI-1 family proteins participate in cell cycle progression by coactivating E2F1-or p53-dependent transcriptional activation. Here, we report the identification of human CDCA4 (also know as SEI-3/Hepp) as a novel target gene of transcription factor E2F and as a repressor of E2F-dependent transcriptional activation. Analysis of CDCA4 promoter constructs showed that an E2F-responsive sequence in the vicinity of the transcription initiation site is necessary for the E2F1-4-induced activation of CDCA4 gene transcription. Chromatin immunoprecipitation analysis demonstrated that E2F1 and E2F4 bound to an E2F-responsive sequence of the human CDCA4 gene. Like TRIP-Br1/p34 SEI-1 and TRIP-Br2 (SEI-2), the transactivation domain of CDCA4 was mapped within C-terminal acidic region 175-241. The transactivation function of the CDCA4 protein was inhibited by E2F1-4 and DP2, but not by E2F5-8. Inhibition of CDCA4 transactivation activity by E2F1 partially interfered with retinoblastoma protein overexpression. Conversely, CDCA4 suppressed E2F1-3-induced reporter activity. CDCA4 (but not acidic region-deleted CDCA4) suppressed E2F1-regulated gene promoter activity. These findings suggest that the CDCA4 protein functions as a suppressor at the E2F-responsive promoter. Small interfering RNA-mediated knockdown of CDCA4 expression in cancer cells resulted in upregulation of cell growth rates and DNA synthesis. The CDCA4 protein was detected in several human cells and was induced as cells entered the G 1 /S phase of the cell cycle. Taken together, our results suggest that CDCA4 participates in the regulation of cell proliferation, mainly through the E2F/retinoblastoma protein pathway.

Control of sleep by a network of cell cycle genes

“…TARA and the Trip-Br family of proteins have been shown to act as coregulators of the E2F1-DP1 transcription complex. [19][20][21][22] However, we did not find evidence for a genetic interaction between E2f1 and tara for sleep regulation (Fig. 2).…”

Oncogenic function of p34SEI-1 via NEDD4-1-mediated PTEN ubiquitination/degradation and activation of the PI3K/AKT pathway

“…p34 SEI-1 is known to act as a transcriptional regulator, cell cycle regulator, senescence inhibitor and apoptosis inhibitor (22,(24)(25)(26)(27)(28)(29). Especially, it plays a critical role in tumor pathogenesis acting as an oncoprotein.…”

CRM1-mediated Nuclear Export Is Required for 26 S Proteasome-dependent Degradation of the TRIP-Br2 Proto-oncoprotein

“…Our group and others have previously demonstrated that some members of this novel family of proto-oncogenes and/or tumor suppressors, such as TRIP-Br1, RBT1, and TRIP-Br3, are themselves tightly controlled during cell cycle progression by regulatory processes that remain elusive (1,5,6). We have also recently shown that the loss and gain of function of the poorly studied TRIP-Br2 protein leads to cell proliferation arrest and tumor progression, respectively (2).…”

“…Although the function of the SERTA domain remains to be elucidated, studies have shown that this motif of TRIP-Br1 binds to cyclin-dependent kinase 4 (CDK4) and facilitates the assembly and activation of cyclin D⅐CDK4 complexes (8). Notably, the C terminus of TRIP-Br proteins is required not only for the stimulation of E2F-mediated transcription by TRIP-Br1, TRIP-Br2, and RBT1 (1,5,9) but also for TRIP-Br3-mediated suppression of E2F-dependent transcription (6).…”

“…TRIP-Br proteins are recruited to the retinoblastoma (Rb) protein-dissociated E2F-1⅐DP-1 complexes on E2F-responsive promoters through physical association with DP-1. PHD zinc finger-and/or bromodomain-containing proteins such as p300/CBP, PCAF, and KRIP-1, present in differing amounts and possessing different binding affinities, have been proposed to compete for binding to TRIP-Br proteins and confer positive or negative regulatory signals to E2F-1⅐DP-1 transcription complexes assembled on E2F-responsive promoters (1,5,6). Antagonism of the TRIP-Br integrator function has been shown recently to elicit a proliferative block and caspase-3-independent cellular subdiploidization, associated with the transcriptional down-regulation of a subset of E2F-responsive genes in vivo (7).…”