Phenotype Specific Analyses Reveal Distinct Regulatory Mechanism for Chronically Activated p53

Abstract

The downstream functions of the DNA binding tumor suppressor p53 vary depending on the cellular context, and persistent p53 activation has recently been implicated in tumor suppression and senescence. However, genome-wide information about p53-target gene regulation has been derived mostly from acute genotoxic conditions. Using ChIP-seq and expression data, we have found distinct p53 binding profiles between acutely activated (through DNA damage) and chronically activated (in senescent or pro-apoptotic conditions) p53. Compared to the classical ‘acute’ p53 binding profile, ‘chronic’ p53 peaks were closely associated with CpG-islands. Furthermore, the chronic CpG-island binding of p53 conferred distinct expression patterns between senescent and pro-apoptotic conditions. Using the p53 targets seen in the chronic conditions together with external high-throughput datasets, we have built p53 networks that revealed extensive self-regulatory ‘p53 hubs’ where p53 and many p53 targets can physically interact with each other. Integrating these results with public clinical datasets identified the cancer-associated lipogenic enzyme, SCD, which we found to be directly repressed by p53 through the CpG-island promoter, providing a mechanistic link between p53 and the ‘lipogenic phenotype’, a hallmark of cancer. Our data reveal distinct phenotype associations of chronic p53 targets that underlie specific gene regulatory mechanisms.

Proliferation Drives Aging-Related Functional Decline in a Subpopulation of the Hematopoietic Stem Cell Compartment

“…No p53 targets were detected in the marker genes of the other five clusters in Figure 1C (see Table S1).

Figure 2Age-Specific Cluster Carries Signature of Pro-proliferative and Anti-proliferative Stimuli(A) Manual annotation of top 20 marker genes with Ras senescence (RIS), apoptosis (Kirschner et al., 2015), and pStat3 and pStat5 datasets (Lau et al., 2015). Red indicates p53, and green indicates pStat targets.(B) KEGG pathway analysis of marker genes for old-specific cluster.

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CDK6 Inhibition: A Novel Approach in AML Management

“…The underlying mechanism includes an altered cytokine secretion and malignant stem cell activation which is regulated by CDK6 in a largely kinase-independent manner. Moreover, apoptotic players are regulated by CDK6 (e.g., B-cell translocation gene 2 (Btg2) [61], phorbol-12-myristate-13-acetate-induced protein 1 (Pmaip1) [62], krueppel-like factor 6 (Klf6) [63,64], activating transcription factor 3 (Atf3) [61,64,65]) and JAK2-V617F + purified Lineage − Sca1 + cKit+ (LSK) cells lacking CDK6 show enhanced apoptosis. CDK6-deficient LSK cells display altered expression of several negative regulators of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling (e.g., NF-κB inhibitor zeta (NFκBiz), suppressor of cytokine signaling 3 (Socs3) [66][67][68][69]).…”

The Power Behind the Throne: Senescence and the Hallmarks of Cancer

“…In contrast, p53 is involved in wider stress responsive contexts, including cell cycle, acute DDR and DNA repair, apoptosis, and metabolism (Levine & Oren 2009). Interestingly, it has recently been shown that chronic activation of p53, such as seen in senescence, drives a distinct transcriptional program to that seen in the acute p53 activation, upon DDR (see sidebar) (Kirschner et al 2015). In addition, p53 has a range of different functions within the senescence context (Johmura & Nakanishi 2016, Rufini et al 2013.…”