CUX1 and E2F1 Regulate Coordinated Expression of the Mitotic Complex Genes Ect2, MgcRacGAP, and MKLP1 in S Phase

Abstract

Rho GTPases are critical for mitosis progression and completion of cytokinesis. During mitosis, the GDP/GTP cycle of Rho GTPases is regulated by the exchange factor Ect2 and the GTPase activating protein MgcRacGAP which associates with the kinesin MKLP1 in the centralspindlin complex. We report here that expression of Ect2, MgcRacGAP, and MKLP1 is tightly regulated during cell cycle progression. These three genes share similar cell cycle-related signatures within their promoter regions: (i) cell cycle gene homology region (CHR) sites located at ؊20 to ؉40 nucleotides of their transcription start sites that are required for repression in G 1 , (ii) E2F binding elements, and (iii) tandem repeats of target sequences for the CUX1 transcription factor. CUX1 and E2F1 bind these three promoters upon S-phase entry, as demonstrated by chromatin immunoprecipitation, and regulate transcription of these genes, as established using promoterluciferase reporter constructs and expression of activated or dominant negative transcription factors. Overexpression of either E2F1 or CUX1 increased the levels of the endogenous proteins whereas small interfering RNA knockdown of E2F1 or use of a dominant negative E2F1 reduced their expression levels. Thus, CUX1, E2F, and CHR elements provide the transcriptional controls that coordinate induction of Ect2, MgcRacGAP, and MKLP1 in S phase, leading to peak expression of these interacting proteins in G 2 /M, at the time they are required to regulate cytokinesis.

MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma

“…CUX1 is a transcription factor that regulates multiple processes including cell cycle progression, chromosomal segregation and cell migration 29,30 . Consistent with the effects of miR122 silencing described above, CUX1 was reported to modulate cell motility and invasion through the control of RhoA activity [31][32][33] . We observed that whereas CUX1 mRNA levels remained unchanged ( Fig.…”

“…This miR122/CUX1/miR214/ZBTB20/ AFP pathway may explain the deregulated AFP expression observed in HCC cells. Additionally, the ability of CUX1 to activate RhoA and to regulate the expression of many proteins involved in cell motility may explain the increased migration and invasiveness associated with malignancy of HCC [31][32][33][34][35][36] . It should be noted that, although this analysis revealed a trend toward inverse correlation between expression of miR122 and expression of AFP, this correlation could not be applied to all cases examined.…”

CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

“…Many transcriptional targets and cellular functions of CUX1 readily suggest mechanisms by which increased p110 or p75 CUX1 expression might promote tumour development and progression, including acceleration of S phase entry 21,22,41,62,63 , stimulation of cell migration and invasion 13,42,[64][65][66] , resistance to apoptosis 14 , and promotion of bipolar mitosis in the presence of supernumerary centrosomes 19 (reviewed in REF. 67).…”

The roles of CUX1 homeodomain proteins in the establishment of a transcriptional program required for cell migration and invasion

“…17 More recently, p110 CUX1 was found to cooperate with E2F1 and E2F2 in the transcriptional activation of several genes involved in DNA replication and progression through S phase and mitosis. 11,18 Chromatin immunoprecipitation assays revealed that CUX1 enhanced the recruitment of E2F factors to the promoter of these genes.…”