Polo-like kinase 4 transcription is activated via CRE and NRF1 elements, repressed by DREAM through CDE/CHR sites and deregulated by HPV E7 protein

Abstract

Infection by oncogenic viruses is a frequent cause for tumor formation as observed in cervical cancer. Viral oncoproteins cause inactivation of p53 function and false transcriptional regulation of central cell cycle genes. Here we analyze the regulation of Plk4, serving as an example of many cell cycle- and p53-regulated genes. Cell cycle genes are often repressed via CDE and CHR elements in their promoters and activated by NF-Y binding to CCAAT-boxes. In contrast, general activation of Plk4 depends on NRF1 and CRE sites. Bioinformatic analyses imply that NRF1 and CRE are central elements of the transcriptional network controlling cell cycle genes. We identify CDE and CHR sites in the Plk4 promoter, which are necessary for binding of the DREAM (DP, RB-like, E2F4 and MuvB) complex and for mediating repression in G0/G1. When cells progress to G2 and mitosis, DREAM is replaced by the MMB (Myb-MuvB) complex that only requires the CHR element for binding. Plk4 expression is downregulated by the p53-p21WAF1/CIP1-DREAM signaling pathway through the CDE and CHR sites. Cell cycle- and p53-dependent repression is abrogated by HPV E7 oncoprotein. Together with genome-wide analyses our results imply that many cell cycle genes upregulated in tumors by viral infection are bound by DREAM through CDE/CHR sites.

Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control

“…Taken together, the cyclin F-mediated regulatory mechanism adds a new layer of cell cycle control in the early response to DNA damage. We therefore propose that the transcriptional suppression mediated by cyclin F serves as an important temporal safeguard maintaining repression of target genes until the p53 response eventually contributes through mechanisms such as the p53-p21-DREAM-CDE/CHR pathway 34,35 . Very interestingly, cyclin F has been shown to be reduced in certain cancer types 36 , whereas B-Myb is overexpressed in several types of cancers 37 .…”

The transcription factor p53: Not a repressor, solely an activator

“…332,335,348,[350][351][352][353] Recently, attention has shifted to the p53-p21-DREAM pathway. [354][355][356][357] The mammalian DREAM complex consists of the pocket proteins p107 or p130, the transcription factors E2F4 or E2F5 and the dimerization partner DP1, as well as the MuvB core composed of RBBP4 and the LIN proteins LIN9, LIN37, LIN52 and LIN54. 341,358,359 The DREAM components E2F4 and p107/p130 have repeatedly been reported to participate in p53-dependent downregulation of cell cycle genes.…”

“…335,345,346,350,352,360,361 In order to evaluate the proposed indirect repression mechanism involving p21, DREAM, or RB/E2F, we searched the literature and found 88 genes that were described to be indirectly regulated by p53 through this mechanism (Table S4). 9,98,248,257,[330][331][332][333][334][335][345][346][347][348][349][350][351][352][353][354][355][356][357][360][361][362][363][364][365][366][367][368][369][370][371] Impressively, 83 (94.3%) genes were confirmed as repressed (Expression Score 2-1) (Table S4). Therefore, in contrast to the direct repression models, the mechanism of indirect repression employing p21, DREAM, or RB/E2F is supported by the genome-wide expression studies.…”

“…374 Importantly, RB/E2F and DREAM are disrupted by HPV E7. 357,375,376 Thus, one would expect that the expression of genes directly targeted by p53 is impaired by HPV E6 but not by E7 expression. In contrast, genes targeted by RB/E2F or DREAM downstream of the p53 pathway are expected to be deregulated similarly by HPV E6 and E7.…”

Multicilin drives centriole biogenesis via E2f proteins

“…In E2f4-null mice, however, the cell cycle was largely unaffected, reflecting extensive genetic overlap with E2f5, but then the mice surprisingly died of respiratory failure due to an early loss of MCCs in the airways (Danielian et al 2007). Since E2f4 can regulate genes required for centriole assembly during cell division (Fischer et al 2014), this observation raised the possibility that Multicilin could act via E2f4 during MCC differentiation.…”