Multiple Roles of p53-Related Pathways in Somatic Cell Reprogramming and Stem Cell Differentiation

Lan, Yi; Lu, Chi-Wei; Hu, Wenwei; Sun, Yvonne; Levine, Arnold J.

doi:10.1158/0008-5472.can-12-1451

Cited by 79 publications

(73 citation statements)

References 38 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…p53 function is rigorously regulated in pluripotent cells to keep a balance between self-renewal and differentiation (17,18). Increased p53 activity generally leads to enhanced differentiation phenotype, mainly through induction of the cell cycle arrest pathways (19,20). As a result, reducing the activity of p53 improves the efficiency of generating induced pluripotent stem cells (21)(22)(23)(24)(25).…”

Section: Significancementioning

confidence: 99%

Lysine methylation represses p53 activity in teratocarcinoma cancer cells

Zhu

Dou

Sammons

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

TP53 (which encodes the p53 protein) is the most frequently mutated gene among all human cancers, whereas tumors that retain the wild-type TP53 gene often use alternative mechanisms to repress the p53 tumor-suppressive function. Testicular teratocarcinoma cells rarely contain mutations in TP53, yet the transcriptional activity of wild-type p53 is compromised, despite its high expression level. Here we report that in the teratocarcinoma cell line NTera2, p53 is subject to lysine methylation at its carboxyl terminus, which has been shown to repress p53's transcriptional activity. We show that reduction of the cognate methyltransferases reactivates p53 and promotes differentiation of the NTera2 cells. Furthermore, reconstitution of methylation-deficient p53 mutants into p53-depleted NTera2 cells results in elevated expression of p53 downstream targets and precocious loss of pluripotent gene expression compared with re-expression of wild-type p53. Our results provide evidence that lysine methylation of endogenous wild-type p53 represses its activity in cancer cells and suggest new therapeutic possibilities of targeting testicular teratocarcinoma.

show abstract

Section: Significancementioning

confidence: 99%

Lysine methylation represses p53 activity in teratocarcinoma cancer cells

Zhu

Dou

Sammons

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In mammals, DNA methylation targets the cytosine in CpG motifs to form 5-methylcytosine contributing to down-regulation of transcription for methylated sequences (10). Epigenetic regulation is strongly associated with the developmental process, whereas its deregulation, such as by disruption of DNA methylation, can be associated with dedifferentiation and carcinogenic processes (11,12).…”

mentioning

confidence: 99%

Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells

Tanne

Muniz

Puzio-Kuter

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Recent studies have demonstrated abundant transcription of a set of noncoding RNAs (ncRNAs) preferentially within tumors as opposed to normal tissue. Using an approach from statistical physics, we quantify global transcriptome-wide motif use for the first time, to our knowledge, in human and murine ncRNAs, determining that most have motif use consistent with the coding genome. However, an outlier subset of tumor-associated ncRNAs, typically of recent evolutionary origin, has motif use that is often indicative of pathogenassociated RNA. For instance, we show that the tumor-associated human repeat human satellite repeat II (HSATII) is enriched in motifs containing CpG dinucleotides in AU-rich contexts that most of the human genome and human adapted viruses have evolved to avoid. We demonstrate that a key subset of these ncRNAs functions as immunostimulatory "self-agonists" and directly activates cells of the mononuclear phagocytic system to produce proinflammatory cytokines. These ncRNAs arise from endogenous repetitive elements that are normally silenced, yet are often very highly expressed in cancers. We propose that the innate response in tumors may partially originate from direct interaction of immunogenic ncRNAs expressed in cancer cells with innate pattern recognition receptors, and thereby assign a previously unidentified danger-associated function to a set of dark matter repetitive elements. These findings potentially reconcile several observations concerning the role of ncRNA expression in cancers and their relationship to the tumor microenvironment.noncoding RNA | genome evolution | cancer immunology

show abstract

“…In some inbred stains of mice, a deletion or knockout of the p53 gene results in up to a third of the female offspring born runted or exocephalic. These female mice have altered imprinting of the insulin-like growth factor (IGF-2) gene in their livers (Yi et al 2012). These observations are consistent with a role for p53 in the fidelity of sexually dimorphic imprinting during development of the embryo.…”

Section: Teratocarcinomasmentioning

confidence: 99%

“…Subsequently, the expression of p53 in stem cells promotes stem cell commitment to differentiation and tissue regeneration. The dedifferentiation of cells to form stem cells occurs more rapidly and in shorter time intervals in the absence of a functional p53 (Yi et al 2012). …”

Section: The Role Of P53 In Self-renewal and Regenerationmentioning

confidence: 99%

“…Yamanaka and colleagues (Takahashi et al 2007) showed that four transcription factors-Myc, KLF-4, Oct-4, and Sox-2 (so-called Yamanaka reprogramming factors)-added to normal mouse or human fibroblasts could result in the production of induced pluripotent stem (iPS) cells that were capable of contributing to most or all tissues of a mouse when they were placed among the inner cell mass cells of a mouse blastocyst. The efficiency of this epigenetic reprograming was increased and the time to carry out this reprograming was decreased in the absence of a functional p53 protein (Yi et al 2012), once again indicating a role for the p53 protein functions in promoting epigenetic stability.…”

mentioning

confidence: 96%

See 1 more Smart Citation