Rescue of key features of the p63-null epithelial phenotype by inactivation of Ink4a and Arf

Su, Xiaohua; Cho, Min Soon; Gi, Young Jin; Ayanga, Bernard; Sherr, Charles J.; Flores, Elsa R.

doi:10.1038/emboj.2009.151

Cited by 67 publications

(79 citation statements)

References 48 publications

(106 reference statements)

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“…It was shown that the efficiency of reprogramming depends on normal cell proliferation. 13,28 Consistent with the reported hypoproliferation of p63 À / À keratinocytes, 39 we observed that p63 À / À MEFs proliferate slower than their WT counterparts (Figures 3a and c). Thus, we tested whether improving proliferation of p63 À / À MEFs would restore their OSK reprogramming efficiency.…”

Section: Resultssupporting

confidence: 89%

“…Moreover, the tumor suppressors p19-Arf and p16-Ink4A, which are known reprogramming barriers in mouse and human fibroblasts, 23,24 were shown to partially mediate skin and limb defects of p63 À / À mice. 39 However, p19 and p16 are again unchanged in p63 À / À MEFs before and during reprogramming (Figure 3e). Thus, the defective OSK and OS reprogramming of p63 À / À MEFs cannot be explained by upregulation of likely reprogramming barriers in this context.…”

Section: Resultsmentioning

confidence: 92%

“…On the other hand, forced DNp73 overexpression was found to significantly improve speed and efficiency of reprogramming of human fibroblasts. 39 As DNp73 is a well-known dominant-negative p53 family member, 32,50 its positive effect on reprogramming is most likely mediated by antagonizing p53 activity. This, however, was not directly tested.…”

Section: Discussionmentioning

confidence: 99%

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ΔNp63 regulates select routes of reprogramming via multiple mechanisms

Petrenko

Nemajerová

et al. 2013

Cell Death Differ

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Somatic cells can be converted into induced pluripotent stem cells (iPSCs) by forced expression of various combinations of transcription factors, but the molecular mechanisms of reprogramming are poorly understood. Specifically, evidence that the reprogramming process can take many distinct routes only begins to emerge. It is definitively established that p53 deficiency greatly enhances reprogramming, revealing p53's barrier function for induced pluripotency, but the role of its homologs p63 and p73 are unknown. Here we report that in stark contrast to p53, p73 has no role in reprogramming. However, p63 is an enabling (rather than a barrier) factor for Oct4, Sox2 and Klf4 (OSK) and Oct4 and Sox2 (OS), but not for Oct4 and Klf4 (OK) reprogramming of mouse embryonic fibroblasts. Specifically, p63 is essential during reprogramming for maximum efficiency, albeit not for the ability to reprogram per se, and is dispensable for maintaining stability and pluripotency of established iPSC colonies. DNp63, but not TAp63, is the principal isoform involved. Loss of p63 can affect reprogramming via several mechanisms such as reduced expression of mesenchymal-epithelial transition and pluripotency genes, hypoproliferation and loss of the most reprogrammable cell populations. During OSK and OS reprogramming, different mechanisms seem to be critical, such as regulation of epithelial and pluripotency genes in OSK reprogramming versus regulation of proliferation in OS reprogramming. Finally, our data reveal three different routes of reprogramming by OSK, OS or OK, based on their differential p63 requirements for iPSC efficiency and pluripotency marker expression. This supports the concept that many distinct routes of reprogramming exist.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 92%

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ΔNp63 regulates select routes of reprogramming via multiple mechanisms

Petrenko

Nemajerová

et al. 2013

Cell Death Differ

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“…As a transcriptional repressor, p63 maintains proliferation of basal epidermal keratinocytes by directly repressing expression of antiproliferative target genes, including 14-3-3s, p16/Ink4a, p19/Arf, p21, and PTEN (Westfall et al 2003;Watt et al 2008;Su et al 2009a;Leonard et al 2011;Ferone et al 2012). In addition to cellcycle-associated genes, p63 inhibits the expression of nonkeratinocyte genes (i.e., mesodermal genes), as well as a number of other genes such as distinct components of the Notch (Notch1, Hes1) and bone morphogenetic protein (BMP) signaling pathways (Smad7) in epidermal keratinocytes (Nguyen et al 2006;De Rosa et al 2009;Shalom-Feuerstein et al 2011).…”

Section: Va Botchkarev and Er Floresmentioning

confidence: 99%

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

Botchkarev

Flores

2014

Cold Spring Harbor Perspectives in Medicine

100

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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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“…DNp63a is an oncogene that suppresses the activity of the Ink 4A /ARF locus [10] and opposes the tumor suppressive effects of cellular senescence [11,12] suggesting a role in oncogenic initiation [13]. TP63 is amplified at the genomic level in 9.7% of head and neck squamous cell carcinomas, 12.9% of serous ovarian carcinomas, 23% of squamous cervical carcinomas and 28.5% of lung squamous cell carcinomas (http://cbioportal.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Mammary Stem Cell Quiescence via Post-Translational Modification of DeltaNp63alpha

DeCastro¹,

Cherukuri²,

DiRenzo³

2012

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE December 2012 REPORT TYPE Annual Summary DATES COVERED 15November2011-14November2012 TITLE AND SUBTITLE Regulation of Mammary Stem Cell Quiescence via Post-Translational 5a. CONTRACT NUMBERModification of DeltaNp63alpha. 5b. GRANT NUMBERW81XWH-11-1-0043 5c. PROGRAM ELEMENT NUMBER AUTHOR(S)Andrew. J DeCastro, B.S., Pratima Cherukuri, M.S., James DiRenzo, PhD.5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: Andrew.J.DeCastro@Dartmouth.edu 5f. WORK UNIT NUMBER PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERDartmouth College, Hanover, NH 03755 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThis document is the Annual Summary Report on the training grant awarded to Andrew DeCastro entitled Regulation of Mammary Stem Cell Quiescence via Post-translational Modification of ∆NP63α. Here, we report our findings of the effects of TGFβ (previously validated as a kinase in our kinome screen) mediated phosphorylation of ∆NP63α on stem cell behavior and mitotic activity. Task 1 aims to determine the effects of wild-type, phospho-ablative and phospho-mimetic alleles of ∆NP63α phosphorylation on stem cell behavior in vitro. Thus far, we demonstrate that stem cell enriched populations, as indicated by ALDH1 activity, contain higher concentrations of ∆NP63α mRNA. In addition, we demonstrate that the anti-clonogenic effects of TGFβ are mediated through phosphorylation of ∆NP63α, which is rescued via ectopic expression of the phospho-ablative mutant ∆NP63α-AA. Task 2 aims to identify putative ∆NP63α-kinases and determine their role in mitotic activation. Here we further characterize TGFβ-mediated phosphorylation of ∆NP63α. We demonstrate that TGFβ phosphorylation of ∆NP63α is a destabilizing event, and dependent on the proteasomal degradation pathway. We also report a non-canonical pathway in which ALK5 (TGF...

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Rescue of key features of the p63-null epithelial phenotype by inactivation of Ink4a and Arf

Cited by 67 publications

References 48 publications

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

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

Regulation of Mammary Stem Cell Quiescence via Post-Translational Modification of DeltaNp63alpha

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