Integration of Notch 1 and Calcineurin/NFAT Signaling Pathways in Keratinocyte Growth and Differentiation Control

Mammucari, Cristina; Vignano, Alice Tommasi di; Sharov, Andrey A.; Neilson, Joel R.; Havrda, Matthew C.; Roop, Dennis R.; Botchkarev, Vladimir A.; Crabtree, Gerald R.; Dotto, G. Paolo

doi:10.1016/j.devcel.2005.02.016

Cited by 169 publications

(176 citation statements)

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“…In mouse keratinocytes, increased Notch1 activity causes growth arrest through induction of p21 WAF1/Cip1 expression by both direct and indirect RBP-J -dependent mechanisms (Rangarajan et al 2001;Mammucari et al 2005). In transient transfection assays of these cells, the ability of activated Notch1 to induce the 2.4-kb promoter of the p21 gene was suppressed by the concomitant overexpression of ⌬N-p63␣, in a dose-dependent fashion (Fig.…”

Section: The Pro-differentiation Function Of Notch Is Counteracted Bymentioning

confidence: 91%

“…Transcriptional repressors of the HES (Hairy Enhancer of Split)/HERP (HES-related repressor protein) family are well-characterized direct targets of Notch/RBP-J activation (Davis and Turner 2001;Iso et al 2003). In mouse keratinocytes, the gene for the cyclin/CDK inhibitor p21 WAF1/Cip1 is also induced by the Notch/RBP-J complex through both a direct and indirect mechanism (Rangarajan et al 2001;Mammucari et al 2005), with p21 WAF1/Cip1 functioning downstream of Notch, as a negative transcriptional regulator of Wnt4 expression (Devgan et al 2005). Notch activation also exerts effects on other pathways important to keratinocyte growth and differentiation; it induces NF-B (Nickoloff et al 2002) and inhibits AP-1 (Chu et al 2002;Talora et al 2002) and ␤-catenin signaling (Nicolas et al 2003;Devgan et al 2005).…”

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confidence: 99%

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Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation

Nguyen¹,

Lefort²,

Mandinova³

et al. 2006

Genes Dev.

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351

411

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Notch signaling promotes commitment of keratinocytes to differentiation and suppresses tumorigenesis. p63, a p53 family member, has been implicated in establishment of the keratinocyte cell fate and/or maintenance of epithelial self-renewal. Here we show that p63 expression is suppressed by Notch1 activation in both mouse and human keratinocytes through a mechanism independent of cell cycle withdrawal and requiring down-modulation of selected interferon-responsive genes, including IRF7 and/or IRF3. In turn, elevated p63 expression counteracts the ability of Notch1 to restrict growth and promote differentiation. p63 functions as a selective modulator of Notch1-dependent transcription and function, with the Hes-1 gene as one of its direct negative targets. Thus, a complex cross-talk between Notch and p63 is involved in the balance between keratinocyte self-renewal and differentiation. Normal tissue homeostasis is determined by a complex interplay between developmental signals and other cell regulatory pathways. Notch cell surface receptors and their ligands belonging to the Delta and Serrate/Jagged families play a crucial role in cell fate determination and differentiation, functioning in a cell-and context-specific manner (Artavanis-Tsakonas et al. 1999). In mammalian cells, Notch activation is generally thought to maintain stem cell potential and inhibit differentiation, thereby promoting carcinogenesis (Artavanis-Tsakonas et al. 1999). However, in specific cell types such as keratinocytes, increased Notch activity causes exit from the cell cycle and commitment to differentiation (Lowell et al. 2000;Rangarajan et al. 2001;Nickoloff et al. 2002), whereas down-modulation or loss of Notch1 function promotes carcinogenesis (Talora et al. 2002;Nicolas et al. 2003).In the human epidermis, localized expression of the Notch-ligand Delta in putative "stem cells" has been proposed to induce commitment of neighboring Notch1-expressing keratinocytes to a "transit-amplifying" phenotype, through a negative feedback mechanism of lateral inhibition (Lowell et al. 2000). On the other hand, in both mouse and human epidermis, Jagged 1/2, Notch1, and Notch2 are coexpressed in differentiating keratinocytes of the supra-basal layers, consistent with a positive feedback loop between these molecules that serves to reinforce and synchronize Notch activation with differentiation (Luo et al. 1997;Rangarajan et al. 2001;Nickoloff et al. 2002).The best characterized "canonical" pathway of Notch activation involves proteolytic cleavage and translocation of the cytoplasmic domain of the receptor to the nucleus, where it associates with the DNA-binding protein RBP-J (CBF-1, CSL), converting it from a repressor

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Section: The Pro-differentiation Function Of Notch Is Counteracted Bymentioning

confidence: 91%

mentioning

confidence: 99%

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation

Nguyen¹,

Lefort²,

Mandinova³

et al. 2006

Genes Dev.

Self Cite

351

411

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show abstract

“…In keratinocytes, Notch signaling increases calcineurin/NFAT activity by downregulating calcipressin, an endogenous calcineurin inhibitor [34]. In turn, calcineurin/ NFAT signaling affects the expression of Notch-responsive genes.…”

Section: Integration and Crosstalk Between Ca 2+ And Other Signallingmentioning

confidence: 99%

Calcium signaling in lymphocytes

Oh‐hora¹,

Rao²

2008

Current Opinion in Immunology

353

282

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In cells of the immune system, calcium signals are essential for diverse cellular functions including differentiation, effector function and gene transcription. After engagement of immunoreceptors such as T-cell and B-cell antigen receptors and the Fc receptors on mast cells and NK cells, the intracellular concentration of calcium ions is increased through the sequential operation of two interdependent processes: depletion of endoplasmic reticulum Ca 2+ stores as a result of binding of inositol trisphosphate (IP 3 ) to IP 3 receptors, followed by "store-operated" Ca 2+ entry through plasma membrane Ca 2+ channels. In lymphocytes, mast cells and other immune cell types, store-operated Ca 2+ entry through specialised Ca 2+ release-activated calcium (CRAC) channels constitutes the major pathway of intracellular Ca 2+ increase. A recent breakthrough in our understanding of CRAC channel function is the identification of STIM and ORAI, two essential regulators of CRAC channel function. This review focuses on the signaling pathways upstream and downstream of Ca 2+ influx (the STIM/ ORAI and calcineurin/ NFAT pathways respectively).

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“…Visualizing hair waves is facilitated by hair cycle dependent changes in integument pigmentation and timed hair loss in nude mice (Militzer, 2001;Suzuki et al, 2003), Msx2 null mice (Ma et al, 2003), calcineurin B1 (Mammucari et al, 2005), etc. As a result, we observe different skin regions cycling through different stages representing different "status" of hair follicles, which can appear as waves of dramatic pattern changes across the adult mouse skin.…”

Section: Traveling Wavementioning

confidence: 99%

“…Notch 1 activation in keratinocytes can go through the RBP or calcineurin B1 pathways. Recently, mice with a calcineurin B1 deletion also showed a cyclic alopecia phenotype (Mammucari et al, 2005). In humans, each hair follicle cycles independently, so there are no wave-like patterns.…”

Section: Traveling Wavementioning

confidence: 99%

Distinct mechanisms underlie pattern formation in the skin and skin appendages

Widelitz

Baker²,

Plikus

et al. 2006

Birth Defects Research Pt C

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SummaryPatterns form with the break of homogeneity, leading to the emergence of new structure or arrangement. There are different physiological and pathological mechanisms which lead to the formation of patterns. Here we first introduce the basics of pattern formation and their possible biological basis. We then discuss different categories of skin patterns and their potential underlying molecular mechanisms. Some patterns, such as the lines of Blaschko and naevus, are based on cell lineage and genetic mosaicism. Other patterns, such as regional specific skin appendages, can be set by distinct combinatorial molecular codes, which in turn may be set by morphogenetic gradients. There are also some patterns, such as the arrangement of hair follicles (hair whorls) and fingerprints, which involve genetics as well as stochastic epigenetic events based on physical-chemical principles. Many appendage primordia are laid out in developmental waves. In the adult, some patterns, such as those involving cycling hair follicles, may appear as traveling waves in mutant mice. Since skin appendages can renew themselves in regeneration, their size and shape can still change in the adult via regulation by hormones and the environment. Some lesion patterns are based on pathological changes involving the above processes and can be used as diagnostic criteria in medicine. Understanding the different mechanisms which lead to patterns on the skin will help us appreciate their full significance in morphogenesis and medical research. Much remains to be learned about complex pattern formation, a level between molecular biology and organism phenotypes.

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Integration of Notch 1 and Calcineurin/NFAT Signaling Pathways in Keratinocyte Growth and Differentiation Control

Cited by 169 publications

References 40 publications

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation

Calcium signaling in lymphocytes

Distinct mechanisms underlie pattern formation in the skin and skin appendages

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