The Role of the p53 Protein in Stem-Cell Biology and Epigenetic Regulation - PubMed (original) (raw)

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The Role of the p53 Protein in Stem-Cell Biology and Epigenetic Regulation

Arnold J Levine et al. Cold Spring Harb Perspect Med. 2016.

Abstract

The p53 protein plays a passive and an active role in stem cells. The transcriptional activities of p53 for cell-cycle arrest and DNA repair are largely turned off in stem cells, but there is some indication that long-term stem-cell viability may require other p53-regulated functions. When p53 is activated in stem cells, it stops cell division and promotes the commitment to a differentiation pathway and the formation of progenitor cells. In the absence of any p53 activity, stem-cell replication continues and mistakes in the normal epigenetic pathway occur at a higher probability. In the presence of a functionally active p53 protein, epigenetic stability is enforced and stem-cell replication is regulated by commitment to differentiation. Over a lifetime of an organism, stem-cell clones compete in a tissue niche for Darwinian replicative advantages and in doing so accumulate mutations that permit stem-cell replication. Mutations in the p53 gene give stem cells this advantage, increase the clonal stem-cell population, and lower the age at which cancers can occur. Li-Fraumeni patients that inherit p53 mutations develop tumors in a tissue-type-specific fashion at younger ages. Throughout the life of a Li-Fraumeni patient, the tumor types that arise occur in tissues where stem cells are active and cell division is most rapid. Thus, p53 mutations that are inherited or occur during developmental life act in stem cells of the mesenchymal and epithelial lineages, whereas p53 mutations that occur in progenitor or differentiated (somatic) cells later in life function in tissues of endodermal origins, indicating that p53 may function differently in different developmental lineages.

Copyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.

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Figures

Figure 1.

Figure 1.

WNT and R-spondin signaling. (A) ZNRF3/RNF43 ubiquitylates the WNT receptor Frizzled, thus slowing WNT signaling. (B) When R-spondin is present, it binds to its receptor LGR5. This results in complex formation with ZNRF3/RNF43 allowing greater accumulation of Frizzled receptor on the plasma membrane and enhancement of WNT signaling.

Figure 2.

Figure 2.

Different functions of the p53 family of genes—p53, p63, p73. Ancestral members of the p53, p63, and p73 family of transcription factors have been found and studied in the invertebrates, in which their primary roles are to protect the germline from DNA damage. In the vertebrates, the three paralogs (p53, p63, and p73) have distinct transcription factor functions and different tissue specificities.

Figure 3.

Figure 3.

Distinct embryonic origin for tumors with high rates of somatic TP53 mutations and tumors frequently associated with germline TP53 mutations. (A) Tissues/organs in which tumors with high rates of TP53 mutations (>35%) occur are indicated by a red arrow (% somatic mutations, numbers in red). Tissues/organs in which tumors frequently develop in subjects who carry a germline TP53 mutation are indicated by a green arrow (% of all cancer diagnoses in mutation carriers, numbers in green). Tumors that are frequent in mutation carriers are different from those that often contain TP53 somatic mutations, with the exception of cancers of the lung and colorectum (dual color red/green arrows), which are somatically mutated on TP53 in >35% of the case, and yet represent each >1.5% of the cancers diagnosed in germline mutation carriers. (B) Inverse relationship between prevalence of somatic mutation in cancers and proportion of the corresponding diagnosis in mutation carriers.

Figure 4.

Figure 4.

Inherited cancer patterns in germline TP53 mutation carriers. (Top) Proportion of all cancers occurring by each year of age in TP53 mutation carriers. (Middle) Temporal distribution of frequent cancers in TP53 mutation carriers. Arrows indicate the age span during which 75% of the cancers occur. Vertical bars in each arrow: median age at diagnosis. CPT, choroid plexus carcinoma; ACC, adrenal cortical carcinoma; RHA, rhabdomyosarcoma; MED, medulloblastoma; OST, osteosarcoma; HAE, hematopoietic malignancies; CNS, brain tumors (excluding CPT and MED); STS, soft tissue sarcoma (excluding RHA and LEI); BRE, breast cancer; CRC, colorectal cancer; LEI, leiomyosarcoma; LUN, lung cancer. (Bottom) Double-ended arrows indicate the phases of low-frequency stimulation (LFS) characterized by different magnitudes of excess risk of cancer as compared with noncarrier populations, including childhood phase (excess cancer risk: 20- to 1000-fold), adult phase (excess cancer risk: five- to 20-fold), and elderly phase (excess cancer risk: one- to fivefold). (Data from IARC TP53 database, germline mutation dataset, version R17;

p53.iarc.fr/DownloadDataset.aspx

.)

Figure 5.

Figure 5.

Tumor spectrum in Li–Fraumeni patients, p53 heterozygous mice, and p53-null mice. Mice with heterozygous or null p53 mutations in the germline show a restricted tumor tissue type similar to Li–Fraumeni patients with germline mutations. Percentage frequency of each tumor type is shown.

Figure 6.

Figure 6.

Development of mutations in thymic lymphomas of p53 knockout mice. Homozygous p53 knockout mice develop phosphatase and tensin homolog (PTEN) mutations in a tissue-specific stem cell before T-cell rearrangement. They then develop thymic lymphomas starting about 9 weeks after birth and go on to accumulate mutations in CDK4/6, cyclins, and the Notch pathway.

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