p63, a Story of Mice and Men

vanBokhoven, Hans; Melino, Gerry; Candi, Eleonora; Declercq, Wim

doi:10.1038/jid.2011.84

Cited by 154 publications

(157 citation statements)

References 113 publications

(115 reference statements)

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“…2) (for review, see Koster and Roop 2007;Vanbokhoven et al 2011;Botchkarev et al 2012;Su et al 2013). p63 induces in epidermal keratinocytes the expression of the genes encoding basal epidermal keratins 5/14, distinct cell adhesion molecules (P-cadherin, integrin-a3, Perp, dystonin, etc.…”

Section: The P53 Family and Its Isoformsmentioning

confidence: 99%

“…(AP-2g, IKK-a, IRF6, HBP1, Runx1, ZNF750), and DNA repair machinery (BRACA2, MRE11, Rad51) (Koster et al 2004;Ihrie et al 2005;Koster and Roop 2007;Lin et al, 2009;Shalom-Feuerstein et al 2011;Vanbokhoven et al 2011;Sen et al 2012). p63 transcriptional activity is also regulated and inhibited by the FoxO transcription factor, which directly binds to p63 protein and prevents its interaction with gene promoters.…”

Section: Va Botchkarev and Er Floresmentioning

confidence: 99%

“…In contrast to p53, mutations of the p63 gene cause numerous ectodermal dysplasia syndromes also associated with craniofacial and limb abnormalities (for review, see Rinne et al 2007;Vanbokhoven et al 2011). Unlike p53 and p63, mutations in the p73 gene are extremely rare; however, p73 is inactivated in cancers epigenetically, that is, via hypermethylation of its promoter (Maas et al 2013).…”

mentioning

confidence: 99%

“…In particular, the structure and role for the p63 gene as a master regulator of the development and maintenance of the stratified epithelia as well as its involvement in the control of aging and tumor growth were shown (reviewed in Koster and Roop 2007;Crum and McKeon 2010;Melino 2011;Vanbokhoven et al 2011;Su et al 2013). Furthermore, the roles of the distinct p63 and p73 isoforms in the control of cell proliferation, differentiation, and apoptosis in the skin were dissected by using a number of genetically engineered mouse models and in vitro analyses.…”

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confidence: 99%

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p53/p63/p73 in the Epidermis in Health and Disease

Botchkarev

Flores

2014

Cold Spring Harbor Perspectives in Medicine

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Although p53 has long been known as the "guardian of the genome" with a role in tumor suppression in many tissues, the discovery of two p53 ancestral genes, p63 and p73, more than a decade ago has triggered a considerable amount of research into the role of these genes in skin development and diseases. In this review, we primarily focus on mechanisms of action of p53 and p63, which are the best-studied p53 family members in the skin. The existence of multiple isoforms and their roles as transcriptional activators and repressors are key to their function in multiple biological processes including the control of skin morphogenesis, regeneration, tumorigenesis, and response to chemotherapy. Last, we provide directions for further research on this family of genes in skin biology and pathology.

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Section: The P53 Family and Its Isoformsmentioning

confidence: 99%

Section: Va Botchkarev and Er Floresmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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p53/p63/p73 in the Epidermis in Health and Disease

Botchkarev

Flores

2014

Cold Spring Harbor Perspectives in Medicine

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“…9 In addition, differential splicing at the C-terminus produces a-, b-(long) and g-(short) isoforms. 10 In the epidermis, abundantly expressed DNp63a protein is the predominant isoform and exerts its critical pro-proliferative/ maintenance function in skin stem cells. [10][11][12][13][14][15] Selective genetic ablation of all DNp63 isoforms 14 or of the long p63a/b isoforms (Wolff et al 16 and references therein) closely reproduces the phenotypes of global p63 À / À mice.…”

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confidence: 99%

p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis

et al. 2014

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In embryogenesis, p63 is essential to develop mammary glands. In the adult mammary gland, p63 is highly expressed in the basal cell layer that comprises myoepithelial and interspersed stem/progenitor cells, and has limited expression in luminal epithelial cells. In adult skin, p63 has a crucial role in the maintenance of epithelial stem cells. However, it is unclear whether p63 also has an equivalent role as a stem/progenitor cell factor in adult mammary epithelium. We show that p63 is essential in vivo for the survival and maintenance of parity-identified mammary epithelial cells (PI-MECs), a pregnancy-induced heterogeneous population that survives post-lactational involution and contain multipotent progenitors that give rise to alveoli and ducts in subsequent pregnancies. p63 þ / À glands are normal in virgin, pregnant and lactating states. Importantly, however, during the apoptotic phase of post-lactational involution p63 þ / À glands show a threefold increase in epithelial cell death, concomitant with increased activation of the oncostatin M/Stat3 and p53 pro-apoptotic pathways, which are responsible for this phase. Thus, p63 is a physiologic antagonist of these pathways specifically in this regressive stage. After the restructuring phase when involution is complete, mammary glands of p63 þ / À mice again exhibit normal epithelial architecture by conventional histology. However, using Rosa LSL-LacZ ;WAP-Cre transgenics (LSL-LacZ, lox-stop-lox b-galactosidase), a genetic in vivo labeling system for PI-MECs, we find that p63 þ / À glands have a 30% reduction in the number of PI-MEC progenitors and their derivatives. Importantly, PI-MECs are also cellular targets of pregnancy-promoted ErbB2 tumorigenesis. Consistent with their PI-MEC pool reduction, one-time pregnant p63 þ / À ErbB2 mice are partially protected from breast tumorigenesis, exhibiting extended tumor-free and overall survival, and reduced tumor multiplicity compared with their p63 þ / þ ErbB2 littermates. Conversely, in virgin ErbB2 mice p63 heterozygosity provides no survival advantage. In sum, our data establish that p63 is an important survival factor for pregnancy-identified PI-MEC progenitors in breast tissue in vivo.

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Mice as Experimental Organisms

Merlo

Altruda

Poli

2012

Encyclopedia of Life Sciences

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The mouse is extensively used as a model system to reproduce human diseases in a mammalian system, and to consequently allow to examine the molecular and pathogenic features of the disease in a context that is as close as possible to the human being. The use of the mouse has been particularly useful in three large areas of experimental pathogenesis: (1) classic monogenic diseases, (2) cancer development and progression and (3) developmental genetics and congenital pathologies. In each of these areas, significant progress has been made in recent years. Here, after a short introduction to the biology of the mouse and its history as a model organism, we summarise the current status of genetic manipulation of the mouse genome, provide an overview of current knowledge and illustrate some recent advancements. Key Concepts: The mouse is a model of choice to study human disease because is relatively easy to handle while being surprisingly similar to humans. The mouse and human genomes share considerable homology. The pluripotency of early embryonic cells is the basis of the possibility to manipulate the mouse genome and obtain animals carrying specific mutations. Current methodology consent to modify the mouse genome in several ways, including conventional, dynamic and inducible mutations. Mouse models of human genetic diseases provide an ideal basis for studying the pathogenic mechanism and testing innovative therapies. Key concept in cancer initiation and progression have been established thanks to mouse models. Experimentally, we can use the mouse to visualise complex processes (cell communication, differentiation fate and embryonic development) in a mammalian system. Embryonic development of Vertebrates is highly conserved, reflecting extensive genome conservation. Pluripotency is also achieved by reprogramming of somatic cells; this has great implication for biology of stem cells and possible innovative therapies.

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p63, a Story of Mice and Men

Cited by 154 publications

References 113 publications

p53/p63/p73 in the Epidermis in Health and Disease

p53/p63/p73 in the Epidermis in Health and Disease

p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis

Mice as Experimental Organisms

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