Conditional ablation of C/EBPβ demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis

Sterneck, Esta; Zhu, Shuyu; Ramı́rez, Ángel; Jorcano, José L.; Smart, Robert C.

doi:10.1038/sj.onc.1209144

Cited by 67 publications

(54 citation statements)

References 31 publications

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“…Although C/EBPa and C/EBPh are 90% similar in their basic leucine zipper domain and are considered to bind the same DNA consensus sequence (1), they have opposite effects on skin tumor development. C/EBPh knockout mice are completely refractory to skin tumorigenesis involving Ras, and our previous studies indicate that C/EBPh can cooperate with Ras to induce transformation (42,58). Thus, it is possible that increased expression of C/EBPh in C/EBPa-deficient epidermis contributes to the enhanced tumor phenotype observed in C/EBPa-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Genetic Ablation of CCAAT/Enhancer Binding Protein α in Epidermis Reveals Its Role in Suppression of Epithelial Tumorigenesis

et al. 2007

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CCAAT/enhancer binding protein A (C/EBPA) is a basic leucine zipper transcription factor that inhibits cell cycle progression and regulates differentiation in various cell types. C/EBPA is inactivated by mutation in acute myeloid leukemia (AML) and is considered a human tumor suppressor in AML. Although C/EBPA mutations have not been observed in malignancies other than AML, greatly diminished expression of C/EBPA occurs in numerous human epithelial cancers including lung, liver, endometrial, skin, and breast, suggesting a possible tumor suppressor function. However, direct evidence for C/EBPA as an epithelial tumor suppressor is lacking due to the absence of C/EBPA mutations in epithelial tumors and the lethal effect of C/EBPA deletion in mouse model systems. To examine the function of C/EBPA in epithelial tumor development, an epidermal-specific C/EBPA knockout mouse was generated. The epidermal-specific C/EBPA knockout mice survived and displayed no detectable abnormalities in epidermal keratinocyte proliferation, differentiation, or apoptosis, showing that C/EBPA is dispensable for normal epidermal homeostasis. In spite of this, the epidermal-specific C/EBPA knockout mice were highly susceptible to skin tumor development involving oncogenic Ras. These mice displayed decreased tumor latency and striking increases in tumor incidence, multiplicity, growth rate, and the rate of malignant progression. Mice hemizygous for C/ EBPA displayed an intermediate-enhanced tumor phenotype. Our results suggest that decreased expression of C/EBPA contributes to deregulation of tumor cell proliferation. C/ EBPA had been proposed to block cell cycle progression through inhibition of E2F activity. We observed that C/EBPA blocked Ras-induced and epidermal growth factor-induced E2F activity in keratinocytes and also blocked Ras-induced cell transformation and cell cycle progression. Our study shows that C/EBPA is dispensable for epidermal homeostasis and provides genetic evidence that C/EBPA is a suppressor of epithelial tumorigenesis. [Cancer Res 2007;67(14):6768-76]

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Section: Discussionmentioning

confidence: 99%

Genetic Ablation of CCAAT/Enhancer Binding Protein α in Epidermis Reveals Its Role in Suppression of Epithelial Tumorigenesis

et al. 2007

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“…Mice expressing A-C/EBP in the basal epidermis mimic some aspects of the C/EBPb knockout mice (26) and the conditional deletion of C/EBPb in the epidermis (28). Each of these mouse models is refractory to papilloma formation.…”

Section: Discussionmentioning

confidence: 99%

“…However, when the C/EBPb null mice were backcrossed into a FVB/N background, they had a scruffy coat phenotype and were slightly smaller than controls (20). Mice with the conditional deletion of C/EBPb in the epidermis are also resistant to carcinogen-induced skin tumorigenesis (28).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of CCAAT/Enhancer Binding Protein Family DNA Binding in Mouse Epidermis Prevents and Regresses Papillomas

Rishi

Orosz

et al. 2007

Cancer Research

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The CCAAT/enhancer binding proteins (C/EBP) are a family of B-ZIP DNA binding proteins that act as transcription factors to regulate growth and differentiation of many cell types, including keratinocytes. To examine the consequences of inhibiting the C/EBP family of transcription factors in skin, we generated transgenic mice that use the tetracycline system to conditionally express A-C/EBP, a dominant negative that inhibits the DNA binding of C/EBP family members. We expressed A-C/EBP in the basal layer of the skin epidermis during a two-step skin carcinogenesis protocol. A-C/EBP expression caused hyperplasia of the basal epidermis and increased apoptosis in the suprabasal epidermis. The mice developed fewer papillomas and had systemic hair loss. A-C/ EBP expression caused C/EBPB protein to disappear whereas C/EBPA, p53, Bax, and caspase-3 protein levels were dramatically up-regulated in the suprabasal layer. Primary keratinocytes recapitulate the A-C/EBP induction of cell growth and increase in p53 protein. A-C/EBP expression after papilloma development caused the papillomas to regress with an associated increase in apoptosis and up-regulation of p53 protein. Furthermore, A-C/EBP-expressing mice heterozygous for p53 were more susceptible to papilloma formation, suggesting that the suppression of papilloma formation has a p53-dependent mechanism. These results implicate DNA binding of C/EBP family members as a potential molecular therapeutic target.

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“…In support of this, the majority of mice with a lung-specific inactivation of C/ EBPa die from respiratory failure at birth, and lungs analyzed just before birth display pulmonary immaturity including disrupted surfactant production (Martis et al, 2006). C/EBPb plays a pivotal role in differentiation of myeloid cells, skin, and adipose tissue (Natsuka et al, 1992;Tanaka et al, 1997;Sterneck et al, 2005;Guerzoni et al, 2006) and in contrast to C/EBPa is thought to promote proliferation (Ramji and Foka, 2002). In addition, C/EBPb is important for the respiratory system by regulating the expression of both inflammatory and lung-specific genes (Cassel et al, 2000a(Cassel et al, , 2002Didon et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Airway epithelial cell differentiation during lung organogenesis requires C/EBPα and C/EBPβ

Roos

Berg

Barton

et al. 2012

Developmental Dynamics

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Background: CCAAT/enhancer‐binding protein (C/EBP)α is crucial for lung development and differentiation of the pulmonary epithelium. Conversely, no lung defects have been observed in C/EBPβ‐deficient mice, although C/EBPβ trans‐activate pulmonary genes by binding to virtually identical DNA‐sequences as C/EBPα. Thus, the pulmonary phenotype of mice lacking C/EBPβ could be explained by functional replacement with C/EBPα. We investigated whether C/EBPα and C/EBPβ have overlapping functions in regulating lung epithelial differentiation during organogenesis. Epithelial differentiation was assessed in mice with a lung epithelial–specific (SFTPC‐Cre‐mediated) deletion of C/EBPα (CebpaΔLE), C/EBPβ (CebpbΔLE), or both genes (CebpaΔLE; CebpbΔLE). Results: Both CebpaΔLE mice and CebpaΔLE; CebpbΔLE mice demonstrated severe pulmonary immaturity compared to wild‐type littermates, while no differences in lung histology or epithelial differentiation were observed in CebpbΔLE mice. In contrast to CebpaΔLE mice, CebpaΔLE; CebpbΔLE mice also displayed undifferentiated Clara cells with markedly impaired protein and mRNA expression of Clara cell secretory protein (SCGB1A1), compared to wild‐type littermates. In addition, ectopic mucus‐producing cells were observed in the conducting airways of CebpaΔLE; CebpbΔLE mice. Conclusions: Our findings demonstrate that C/EBPα and C/EBPβ play pivotal, and partly overlapping roles in determining airway epithelial differentiation, with possible implications for tissue regeneration in lung homeostasis and disease. Developmental Dynamics 241:911–923, 2012. © 2012 Wiley Periodicals, Inc.

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Conditional ablation of C/EBPβ demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis

Cited by 67 publications

References 31 publications

Genetic Ablation of CCAAT/Enhancer Binding Protein α in Epidermis Reveals Its Role in Suppression of Epithelial Tumorigenesis

Genetic Ablation of CCAAT/Enhancer Binding Protein α in Epidermis Reveals Its Role in Suppression of Epithelial Tumorigenesis

Inhibition of CCAAT/Enhancer Binding Protein Family DNA Binding in Mouse Epidermis Prevents and Regresses Papillomas

Airway epithelial cell differentiation during lung organogenesis requires C/EBPα and C/EBPβ

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