Mek1/2 MAPK Kinases Are Essential for Mammalian Development, Homeostasis, and Raf-Induced Hyperplasia

Scholl, Florence A.; Dumesic, Phillip A.; Barragan, Deborah I.; Harada, Kazutoshi; Bissonauth, Vickram; Charron, Jean; Khavari, Paul A.

doi:10.1016/j.devcel.2007.03.009

Cited by 131 publications

(145 citation statements)

References 44 publications

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“…The embryonic death of Mek1;Mek2 mutants precludes the study of their function at later stages. Using a Mek1 conditional allele and lineage-specific Cre mice, the function of both MEK1 and MEK2 proteins in numerous processes has been unveiled, highlighting the broad role of the ERK/MAPK pathway throughout life (Li et al, 2012;Newbern et al, 2008;Scholl et al, 2007;Yamashita et al, 2011).…”

Section: Mek2mentioning

confidence: 99%

Crucial requirement of ERK/MAPK signaling in respiratory tract development

et al. 2014

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There was an error published in Development 141, 3197-3211.In the key for Fig. 3C, the grey bars were labelled with the incorrect genotype name. The correct genotype is Mek1 +/flox ;Mek2+/cre . This error does not affect the conclusions of the paper.The authors apologise to readers for this mistake. In vitro, the loss of Mek function in lung mesenchyme did not interfere with lung growth and branching, suggesting that both the reduced intrathoracic space due to the dysmorphic rib cage and the omphalocele impaired lung development in vivo. Conversely, Mek mutation in the respiratory epithelium caused lung agenesis, a phenotype resulting from the direct impact of the ERK/MAPK pathway on cell proliferation and survival. No tracheal epithelial cell differentiation occurred and no SOX2-positive progenitor cells were detected in mutants, implying a role for the ERK/MAPK pathway in trachea progenitor cell maintenance and differentiation. Moreover, these anomalies were phenocopied when the Erk1 and Erk2 genes were mutated in airway epithelium. Thus, the ERK/MAPK pathway is required for the integration of mesenchymal and epithelial signals essential for the development of the entire respiratory tract.

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Section: Mek2mentioning

confidence: 99%

Crucial requirement of ERK/MAPK signaling in respiratory tract development

et al. 2014

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“…The Mek/Erk, Akt, and p38 pathways have been shown to be directly downstream of Ras activation in a variety of settings, including oncogenic transformation (45,46). In control skin, phosphorylated Erk (p-Erk) was found in basal cells of the IFE and in the bulges and ORS of hair follicles (Fig.…”

Section: Resultsmentioning

confidence: 99%

Defining the origins of Ras/p53-mediated squamous cell carcinoma

White

Tran

Khuu

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The precise identity of cancer cells of origin and the molecular events of tumor initiation in epidermal squamous cell carcinoma (SCC) are unknown. Here we show that malignancy potential is related to the developmental capacity of the initiating cancer cell in a genetically defined, intact, and inducible in vivo model. Specifically, these data demonstrate that SCCs can originate from inside the hair follicle stem cell (SC) niche or from immediate progenitors, whereas more developmentally restricted progeny, the transit amplifying (TA) cells, are unable to generate even benign tumors in the same genetic context. Using a temporal model of tumorigenesis in situ, we highlight the phenotypes of cancer progression from the hair follicle SC niche, including hyperplasia, epithelial to mesenchymal transition, and SCC formation. Furthermore, we provide insights into the inability of hair follicle TA cells to respond to tumorigenic stimuli. mouse models of cancer | tumor initiating cells | epidermal stem cells S quamous cell carcinoma (SCC), a common type of nonmelanoma skin cancer, harbors significant risk of metastasis that can eventually lead to death (1). Permanent treatment and prevention of SCC requires an improved understanding of the unique cell types capable of initiating these malignancies and the mechanisms that underlie their transformation. Mutations in the Ras gene family are found in 30% of all human cancers and are often found in human cases of SCC (2-4). Numerous animal studies have extended the understanding of SCC by demonstrating a causative role for the Ras family in the development of SCC. In these mouse models, Ras signaling has been shown to be sufficient to drive epidermal tumorigenesis through either overexpression or targeted expression of an oncogenic form of Hras or Kras. These studies have targeted broad epidermal cell populations that include stem cells (SCs), as well as cells of the outer root sheath (ORS) and interfollicular epidermis (IFE) (4-9). Among these, a landmark article indicated that the SCC cells of origin reside in the hair follicle rather than the IFE (5). However, the keratin promoter used to drive oncogenic Ras expression did not allow for a direct determination of the cancer cell of origin amongst the different cell types in the hair follicle. The candidates for an SCC cell of origin therefore remained follicular SCs, ORS cells, transit amplifying (TA) cells in the matrix, and the differentiated cells of the inner root sheath (IRS) and hair shaft. In addition, other studies have shown that lineagerestricted or differentiated cells of the IFE are sufficient to serve as cancer cells of origin when subjected to supraphysiological levels of Ras activity at sites of mechanical stress (10). These high levels of Ras expression, however, are not normally found in human cases of SCC (10, 11). Between follicular SCs and TA cells, it is not clear whether one or both are capable of initiating tumorigenesis. Thus, we sought to directly compare the malignancy potential between follicular ...

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“…Concerning MEK1, in the adult mouse only double invalidation of MEK1 and MEK2 led to various disorders and rapid death, and furthermore only one allele of MEK either MEK1 or MEK2 was sufficient to allow normal skin development. 74 At least in skin MEK1 and MEK2 are fully redundant. Concerning B-Raf, animals lacking B-Raf died from neurological problems 21 days post-birth.…”

Section: Total Erk Activity Controls Cell Proliferationmentioning

confidence: 99%

Total ERK1/2 activity regulates cell proliferation

LeFloch¹,

Pouysségur²,

Lenormand³

2009

Cell Cycle

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Regulating ERK activity is essential for normal cell proliferation to occur. In mammals and most vertebrates ERK activity is provided by ERK1 and ERK2 that are highly similar, ubiquitously expressed and share activators and substrates. By combining single and double silencings of ERK1 and ERK2 we recently demonstrated that the apparent dominant role of ERK2 to regulate cell proliferation was due to its markedly higher expression level than ERK1. The contribution of ERK1 was revealed when ERK2 activation was clamped to avoid compensating over-activation of ERK2. We found no evidences in the literature for insulated isoform-specific modules in the Ras/Raf/MEK signaling cascade that could activate specifically ERK1 or ERK2. Obviously in frogs all signal integration and fine modulation provided by three Ras and three Raf isoforms is conducted by only one MEK and one ERK isoform. In mammals, ERK1 and ERK2 display similar specific activities and are activated respectively to their expression levels. After integrating signals from Ras, Raf and MEK isoforms, ERK1 and ERK2 regulate positively cell proliferation according to their expression levels.

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Mek1/2 MAPK Kinases Are Essential for Mammalian Development, Homeostasis, and Raf-Induced Hyperplasia

Cited by 131 publications

References 44 publications

Crucial requirement of ERK/MAPK signaling in respiratory tract development

Crucial requirement of ERK/MAPK signaling in respiratory tract development

Defining the origins of Ras/p53-mediated squamous cell carcinoma

Total ERK1/2 activity regulates cell proliferation

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