A mutation in stratifin is responsible for the repeated epilation (Er) phenotype in mice

Herron, Bruce J.; Liddell, Rebecca A.; Parker, April; Grant, Sarah; Kinne, Jennifer; Fisher, Jill K.; Siracusa, Linda D.

doi:10.1038/ng1652

Cited by 68 publications

(70 citation statements)

References 9 publications

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“…A radiation-induced mouse mutant strain known as Repeated-epilation (Er) exhibits a severe skin polarization defect resulting from the expression of a truncated form of 14-3-3σ (26,27). Consistent with these initial observations, targeted disruption of 14-3-3σ in mouse mammary gland results in a dramatic loss of epithelial polarity resulting from the absence of 14-3-3σ-dependent relocalization of the Par3 polarity complex to the apical surface (28).…”

Section: Loss Of 14-3-3s Results In Both Accelerated Erbb2 Mammary Tusupporting

confidence: 67%

“…The dramatic and reversible effects of 14-3-3σ on epithelial polarity are consistent with observations made with the Er mouse mutant that harbors a truncated version of 14-3-3σ. Mice heterozygous for this mutant form of 14-3-3σ possess severely disrupted epithelial stratification in the skin (26,27). The concept that genes involved in regulating polarity can impact on tumorigenesis is supported by several recent observations.…”

Section: Discussion Loss Of 14-3-3s Is a Critical Event In Erbb2 Mammsupporting

confidence: 51%

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Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

Chen

Zuo

et al. 2012

Cancer Discovery

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is a putative tumor suppressor involved in cell-cycle progression and epithelial polarity. We demonstrate that loss of one or both copies of the conditional 14-3-3σ allele results in accelerated mammary and salivary tumorigenesis in mice expressing an activated erbB2 oncogene under the endogenous erbB2 promoter. Significantly, the majority of tumors bearing a single conditional 14-3-3σ allele lose expression of the remaining 14-3-3σ allele, which is associated with epigenetic methylation of the 14-3-3σ locus. In addition to accelerated tumor onset, in a mouse mammary tumor virusdriven ErbB2 tumor model, loss of 14-3-3σ results in enhanced metastatic phenotype that is correlated with loss of cellular junctions. Taken together, these results provide compelling evidence that 14-3-3σ is a potent tumor suppressor involved in ErbB2-driven breast cancer initiation and metastasis.siGNiFicaNce: 14-3-3σ has been identified as a normal mammary epithelial cell marker frequently downregulated during neoplastic development. Consistent with its potential role as a tumor suppressor, we demonstrate that targeted disruption of 14-3-3σ in a number of epithelial tissues can profoundly impact both the initiation and metastatic phases of ErbB2-mediated tumor progression through modulation of a number of distinct signaling networks. Cancer Discovery; 2(1); 68-81.

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Section: Loss Of 14-3-3s Results In Both Accelerated Erbb2 Mammary Tusupporting

confidence: 67%

Section: Discussion Loss Of 14-3-3s Is a Critical Event In Erbb2 Mammsupporting

confidence: 51%

Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

Chen

Zuo

et al. 2012

Cancer Discovery

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“…[11][12][13][14] Embryos from each of these groups exhibit shiny, taut skin stemming from the dysfunctional terminal differentiation of the epidermal keratinocytes, and similar limb and skeletal defects. Histological examination of the epidermis of Irf6 null embryos revealed an expanded spinous layer which aberrantly expressed Keratin 14 and p63, both markers of the basal layer which are normally silenced during cell cycle arrest and terminal differentiation of the desquamating keratinocytes.…”

Section: Similarities Between Irf6 14-3-3σ and Ikkα Knockout Micementioning

confidence: 99%

IRF6 in development and disease: A mediator of quiescence and differentiation

Bailey

Hendrix²

2008

Cell Cycle

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Post utero development of the mammary gland is a complex developmental process characterized by states of rapid cell proliferation (branching morphogenesis) followed by functional differentiation (lactation) and the consequent apoptosis (involution) of the secretory mammary epithelial cell. This process is cyclical, such that involution returns the mammary gland to a near-virgin-like state capable of responding to morphogenic cues with each consecutive pregnancy. Importantly, many of the regulatory processes which oversee mammary gland development are corrupted or otherwise compromised during the development of breast cancer. For example, Interferon Regulatory Factor 6 (IRF6) is a novel protein with growth inhibitory properties that was initially identified in mammary epithelial cells through its interaction with maspin, a known tumor suppressor in normal breast tissue. Recent findings from our laboratory suggest that IRF6 functions synergistically with maspin to regulate mammary epithelial cell differentiation by acting on the cell cycle. This perspective focuses on the possible involvement of IRF6 in promoting differentiation by regulating exit from the cell cycle and entry into the G(0) phase of cellular quiescence, and how these new findings shed light on normal mammary gland development and the initiation and progression of breast cancer.

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“…Unique to 14-3-3 proteins, SFN expression is largely restricted to skin and other epithelia. A SFN mutation causes the repeated epilation (Er) mouse phenotype, characterized by a hyperproliferative epidermis with impaired differentiation (Herron et al 2005;Li et al 2005). In keratinocytes, SFN is involved with diverse and far-ranging effects, including protein kinase C signaling (Dellambra et al 2000), regulation of epidermal cell growth through mTOR/AKT (Kim et al 2006), and extracellular signaling to fibroblasts (Ghahary et al 2005).…”

Section: Calml5 Interacts With Sfnmentioning

confidence: 99%

CALML5 is a ZNF750- and TINCR-induced protein that binds stratifin to regulate epidermal differentiation

et al. 2015

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Outward migration of epidermal progenitors occurs with induction of hundreds of differentiation genes, but the identities of all regulators required for this process are unknown. We used laser capture microdissection followed by RNA sequencing to identify calmodulin-like 5 (CALML5) as the most enriched gene in differentiating outer epidermis. CALML5 mRNA was up-regulated by the ZNF750 transcription factor and then stabilized by the long noncoding RNA TINCR. CALML5 knockout impaired differentiation, abolished keratohyalin granules, and disrupted epidermal barrier function. Mass spectrometry identified SFN (stratifin/14-3-3σ) as a CALML5-binding protein.CALML5 interacts with SFN in suprabasal epidermis, cocontrols 13% of late differentiation genes, and modulates interaction of SFN to some of its binding partners. A ZNF750-TINCR-CALML5-SFN network is thus essential for epidermal differentiation.

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A mutation in stratifin is responsible for the repeated epilation (Er) phenotype in mice

Cited by 68 publications

References 9 publications

Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

IRF6 in development and disease: A mediator of quiescence and differentiation

CALML5 is a ZNF750- and TINCR-induced protein that binds stratifin to regulate epidermal differentiation

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