DREAM and RB cooperate to induce gene repression and cell-cycle arrest in response to p53 activation

Abstract

Most human cancers acquire mutations causing defects in the p53 signaling pathway. The tumor suppressor p53 becomes activated in response to genotoxic stress and is essential for arresting the cell cycle to facilitate DNA repair or to initiate apoptosis. p53-induced cell cycle-arrest is mediated by expression of the CDK inhibitor p21WAF1/Cip1, which prevents phosphorylation and inactivation of the pocket proteins RB, p130, and p107. In a hypophosphorylated state, pocket proteins bind to E2F factors forming RB-E2F and DREAM transcriptional repressor complexes. Here, we analyze the influence of RB and DREAM on p53-induced gene repression and cell-cycle arrest. We show that abrogation of DREAM function by knockout of the DREAM component LIN37 results in a reduced repression of cell-cycle genes. We identify the genes repressed by the p53-DREAM pathway and describe a set of genes that is downregulated by p53 independent of LIN37/DREAM. Most strikingly, p53-dependent repression of cell-cycle genes is completely abrogated in LIN37−/−;RB−/− cells leading to a loss of the G1/S checkpoint. Taken together, we show that DREAM and RB are key factors in the p53 signaling pathway to downregulate a large number of cell-cycle genes and to arrest the cell cycle at the G1/S transition.

Bioinformatics Analysis of Prognostic value and prospective Pathway signal of miR-30a in Ovarian Cancer

“…The Tp53 gene encodes a tumor suppressor protein that includes transcriptional activation, DNA binding and oligomerization domains. The coding protein regulates the expression of target genes in response to a variety of cellular stress, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair or metabolic changes (24). Hurley et al (25) reported that the sensitivity and speci city of the TP53 and PAX8 joint detection of ovarian cancer were 56% and 98%,…”

A 16-CpG-based Prognostic Signature for Colorectal Cancer

“…This raises a very interesting question: the overall level in tumor tissue may be hypermethylated, but it is hypomethylated at certain important sites. Since DNA methylation represents a molecular mechanism related to gene inhibition, it is believed that methylation in cancer may promote tumor phenotype by inhibiting genes that are initially active in the source tissues, especially those related to tumor suppressor factors, such as Rb, P53 etc [23,24]. On the other hand, the other hypomethylation sites are potentially associated with oncogene-directed methylation-associated gene-repression pathways, taking Myc, Ras and Src as examples [25][26][27].…”

Prognostic Values and Prospective Pathway Signaling of miR-30a in Ovarian Cancer: A Study Based on Gene Expression Omnibus and Bioinformatics Analysis

“…The Tp53 gene encodes a tumor suppressor protein that includes transcriptional activation, DNA binding and oligomerization domains. The coding protein regulates the expression of target genes in response to a variety of cellular stress, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair or metabolic changes (24). Hurley et al (25) reported that the sensitivity and specificity of the TP53 and PAX8 joint detection of ovarian cancer were 56% and 98%, respectively.…”