ΔNp63α promotes cellular quiescence via induction and activation of Notch3

Kent, Sierra; Hutchinson, Justine A.; Balboni, Amanda; DeCastro, Andrew; Cherukuri, Pratima; DiRenzo, James

doi:10.4161/cc.10.18.17300

Cited by 23 publications

(24 citation statements)

References 54 publications

(27 reference statements)

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“…DNp63 promotes the expansion of breast cancer stem cell subpopulations through direct transactivation of the Notch1 promoter (53). Furthermore, Kent and colleagues (38) have reported increased Notch3 abundance upon DNp63 overexpression in an immortalized model of mammary stem cells. Although Notch3 must be formally validated as a direct p63 target in this model system, it appears that Notch signaling mediates DNp63-induced quiescence of mammary stem cells.…”

Section: Notch Pathwaymentioning

confidence: 96%

“…DNp63 affects the Notch signaling by regulating the expression of a number of components of the pathway, including the Notch1, Notch3, Jag1, Jag2, and Hes1 genes (22,32,38,53,68) (Table 1 and Fig. 4C).…”

Section: Notch Pathwaymentioning

confidence: 97%

“…In the normal mammary gland, p63 is confined to the basal/myoepithelial compartment (36). DNp63 preserves the self-renewing capacity of mammary stem cells, partially by promoting their quiescent state (26,(37)(38)(39). DNp63 and TAp63 isoforms are present in mouse mammary stem and progenitor cells, respectively.…”

Section: Mammary Glandmentioning

confidence: 99%

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Maintaining epithelial stemness with p63

et al. 2015

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In stratified epithelial and glandular tissues, homeostasis relies on the self-renewing capacity of stem cells, which are within the basal layer. The p53 family member p63 is an indispensable transcription factor for epithelial morphogenesis and stemness. A splice variant of the transcription factor p63 that lacks an amino-terminal domain, ΔNp63, is selectively found in the basal compartments of several ectoderm-derived tissues such as stratified and glandular epithelia, in which it is required for the replenishment of stem cells. Thus far, the transcriptional programs downstream of p63 in stemness regulation remain incompletely defined. Unveiling the molecular basis of stem cell self-renewal may be relevant in understanding how this process may contribute to cancer development. In this review, we specifically highlight experimental investigations, which suggest that p63 is a marker of normal epithelial stem cells and describe p63 transcriptional targets that may be involved in stemness regulation. Finally, we discuss relevant findings implicating p63 in epithelial cancer stem cell biology.

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Section: Notch Pathwaymentioning

confidence: 96%

Section: Notch Pathwaymentioning

confidence: 97%

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Maintaining epithelial stemness with p63

et al. 2015

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“…For example, selective expansion of the pool of basal cells can be achieved by downregulation of endogenous Notch3 (Kent et al, 2011). Once expanded, these cells can be converted into parabasal cells by local activation of Notch3 signaling and subsequently differentiate.…”

Section: Discussionmentioning

confidence: 99%

Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors

et al. 2015

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Basal cells are multipotent airway progenitors that generate distinct epithelial cell phenotypes crucial for homeostasis and repair of the conducting airways. Little is known about how these progenitor cells expand and transition to differentiation to form the pseudostratified airway epithelium in the developing and adult lung. Here, we show by genetic and pharmacological approaches that endogenous activation of Notch3 signaling selectively controls the pool of undifferentiated progenitors of upper airways available for differentiation. This mechanism depends on the availability of Jag1 and Jag2, and is key to generating a population of parabasal cells that later activates Notch1 and Notch2 for secretory-multiciliated cell fate selection. Disruption of this mechanism resulted in aberrant expansion of basal cells and altered pseudostratification. Analysis of human lungs showing similar abnormalities and decreased NOTCH3 expression in subjects with chronic obstructive pulmonary disease suggests an involvement of NOTCH3-dependent events in the pathogenesis of this condition.

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“…Presently the relationship between this amplification and cancer initiation is unknown, however DNp63a is a survival factor that opposes a pro-apoptotic gene expression program [15,16] suggesting a correlation between TP63 amplification and therapeutic resistance. Other studies implicate DNp63a in cellular quiescence [17], which may account for the broad-spectrum resistance of squamous carcinomas [17], which may account for the broad-spectrum resistance to cytotoxic therapeutics. These studies implicate DNp63a in a diverse array of processes associated with cancer initiation and progression and this highlights the need to identify cellular signals governing these diverse activities.…”

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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ΔNp63α promotes cellular quiescence via induction and activation of Notch3

Cited by 23 publications

References 54 publications

Maintaining epithelial stemness with p63

Maintaining epithelial stemness with p63

Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors

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

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