ING2 regulates the onset of replicative senescence by induction of p300-dependent p53 acetylation

ING2 is a candidate tumor suppressor gene that can activate p53 by enhancing its acetylation. Here, we demonstrate that ING2 is also involved in p53-mediated replicative senescence. ING2 protein expression increased in late-passage human primary cells, and it colocalizes with serine 15-phosphorylated p53. ING2 and p53 also complexed with the histone acetyltransferase p300. ING2 enhanced the interaction between p53 and p300 and acted as a cofactor for p300-mediated p53 acetylation. The level of ING2 expression directly modulated the onset of replicative senescence. While overexpression of ING2 induced senescence in young fibroblasts in a p53-dependent manner, expression of ING2 small interfering RNA delayed the onset of senescence. Hence, ING2 can act as a cofactor of p300 for p53 acetylation and thereby plays a positive regulatory role during p53-mediated replicative senescence.     

microRNAs与TP53基因调控网络研究进展

TP53基因(编码p53蛋白)作为一个重要的抑瘤基因,通过调控一系列信号转导通路广泛参与了多种恶性肿瘤的发生发展,一直是肿瘤分子生物学研究领域的热点.最近的研究发现,microRNAs(miRNAs)参与了TP53的信号通路,它们之间存在着复杂的调控网络.一方面,p53通过调控一些miRNAs的转录及转录后成熟,促进细胞周期阻滞、诱导细胞凋亡和衰老,抑制肿瘤发生.另一方面,许多miRNAs,如miR-25、miR-30d、miR-125b和miR-504等可直接调控p53的表达与活性,参与TP53信号通路的调节,还有一些miRNAs则通过调节p53上下游基因,发挥重要的生物学功能.其中,最具有代表性的是miR-34家族,它们受p53直接调控并参与TP53信号通路,通过靶向抑制多个TP53信号通路关键分子的表达,发挥抑瘤作用.此外,它们还可以通过抑制沉默信息调节子,增强p53的活性,反馈调节TP53信号通路.miRNAs与TP53之间调控网络的研究,是对TP53抑瘤机制的重要补充.     

Near‐genomewide RNAi screening for regulators of BRAFV600E‐induced senescence identifies RASEF,a gene epigenetically silenced in melanoma

The activation of oncogenes in primary cells blocks proliferation by inducing oncogene‐induced senescence (OIS), a highly potent in vivo tumor‐suppressing program. A prime example is mutant BRAF, which drives OIS in melanocytic nevi. Progression to melanoma occurs only in the context of additional alteration(s) like the suppression of PTEN, which abrogates OIS. Here, we performed a near‐genomewide short hairpin (sh)RNA screen for novel OIS regulators and identified by next generation sequencing and functional validation seven genes. While all but one were upregulated in OIS, depletion of each of them abrogated BRAF^V600E‐induced arrest. With genome‐wide DNA methylation analysis, we found one of these genes, RASEF, to be hypermethylated in primary cutaneous melanomas but not nevi. Bypass of OIS by depletion of RASEF was associated with suppression of several senescence biomarkers including senescence‐associated (SA)‐β‐galactosidase activity, interleukins, and tumor suppressor p15^INK4B. Restoration of RASEF expression inhibited proliferation. These results illustrate the power of shRNA OIS bypass screens and identify a potential novel melanoma suppressor gene.     

A PTCH1 Homolog Transcriptionally Activated by p53 Suppresses Hedgehog Signaling

The p53-mediated responses to DNA damage and the Hedgehog (Hh) signaling pathway are each recurrently dysregulated in many types of human cancer. Here we describe PTCH53, a p53 target gene that is homologous to the tumor suppressor gene PTCH1 and can function as a repressor of Hh pathway activation. PTCH53 (previously designated PTCHD4) was highly responsive to p53 in vitro and was among a small number of genes that were consistently expressed at reduced levels in diverse TP53 mutant cell lines and human tumors. Increased expression of PTCH53 inhibited canonical Hh signaling by the G protein-coupled receptor SMO. PTCH53 thus delineates a novel, inducible pathway by which p53 can repress tumorigenic Hh signals.     

NORE1A is a double barreled Ras senescence effector that activates p53 and Rb

Although Ras is a potent oncogene in human tumors it has the paradoxical ability to promote Oncogene Induced Senescence (OIS). This appears to serve as a major barrier to Ras driven transformation in vivo. The signaling pathways used by Ras to promote senescence remain relatively poorly understood, but appear to invoke both the p53 and the Rb master tumor suppressors. Exactly how Ras communicates with p53 and Rb has remained something of a puzzle. NORE1A is a direct Ras effector that is frequently downregulated in human tumors. We have now found that it serves as a powerful Ras senescence effector. Moreover, we have defined signaling mechanisms that allows Ras to control both p53 and Rb post-translational modifications via the NORE1A scaffolding molecule. Indeed, NORE1A can be detected in complex with both p53 and Rb. Thus, by coupling Ras to both tumor suppressors, NORE1A forms a major component of the Ras senescence machinery and serves as the missing link between Ras and p53/Rb.