RB, p130 and p107 differentially repress G1/S and G2/M genes after p53 activation

Abstract

Cell cycle gene expression occurs in two waves. The G1/S genes encode factors required for DNA synthesis and the G2/M genes contribute to mitosis. The Retinoblastoma protein (RB) and DREAM complex (DP, RB-like, E2F4 and MuvB) cooperate to repress all cell cycle genes during G1 and inhibit entry into the cell cycle. DNA damage activates p53 leading to increased levels of p21 and inhibition of cell cycle progression. Whether the G1/S and G2/M genes are differentially repressed by RB and the RB-like proteins p130 and p107 in response to DNA damage is not known. We performed gene expression profiling of primary human fibroblasts upon DNA damage and assessed the effects on G1/S and G2/M genes. Upon p53 activation, p130 and RB cooperated to repress the G1/S genes. In addition, in the absence of RB and p130, p107 contributed to repression of G1/S genes. In contrast, G2/M genes were repressed by p130 and p107 after p53 activation. Furthermore, repression of G2/M genes by p107 and p130 led to reduced entry into mitosis. Our data demonstrates specific roles for RB, p130-DREAM, and p107-DREAM in p53 and p21 mediated repression of cell cycle genes.

Biosafety evaluation of culture-expanded human chondrocytes with growth factor cocktail: a preclinical study

“…Of all cell cycle regulators, the p53 transcription factor stands out as a key tumour suppressor and a vital controller of different signalling pathways involved in tumorigenesis 43 . As a main DDR protein, p53 triggers cell cycle arrest to allow for DNA repair, senescence and apoptosis 48 . Therefore, increased expression of p53 above the basal level is indicative of increased various types of stresses.…”

“…Therefore, increased expression of p53 above the basal level is indicative of increased various types of stresses. When p53 is activated, it interacts with p21 (cyclin-dependent kinase inhibitor) to inhibit cdk2 hence arresting cell cycle at G1 and G2/M 48 . Inhibiting cdk2 causes dephosphorylation of the tumour suppressor pRB 48 , 49 .…”

“…When p53 is activated, it interacts with p21 (cyclin-dependent kinase inhibitor) to inhibit cdk2 hence arresting cell cycle at G1 and G2/M 48 . Inhibiting cdk2 causes dephosphorylation of the tumour suppressor pRB 48 , 49 . pRB protein interacts with E2F transcription factor when dephosphorylated forming a complex, thus halting cell cycle progression at G1 as E2F is essential for transcription of genes controlling the cell cycle progress 48 , 49 .…”

Prediction of cancer driver genes through network-based moment propagation of mutation scores

“…For the remaining six genes, five (CASP1, CASP14, RBL1, HNF4A and RALA) had weaker links (e.g. expression linked or pathway membership), but no clear experimental evidence ( Gouravani et al , 2020 ; Krajewska, 2005 ; Schade et al , 2019 ; Seibold et al , 2019 ; Wang et al , 2020 ).…”

Dissecting the DNA binding landscape and gene regulatory network of p63 and p53

“…In agreement with the tumor suppressor role of p53 and the oncogenic role of p63, we find that cell cycle genes are antagonistically regulated by p53 and p63 (Figure 2A and 4A). On the one hand, cell cycle genes are well-known to be down-regulated by p53 indirectly through the cyclin-dependent kinase inhibitor p21 and the cell cycle repressor complexes DREAM and RB-E2F (Fischer et al, 2016a(Fischer et al, , 2016bSchade et al, 2019;Uxa et al, 2019). On the other hand, cell cycle genes are down-regulated upon loss of p63 and this p63-dependent regulation reportedly occurs through regulating p21 signaling and the DREAM component p130 (McDade et al, 2011;Truong et al, 2006).…”