Selective Role for Mek1 but not Mek2 in the Induction of Epidermal Neoplasia

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

doi:10.1158/0008-5472.can-08-1963

Cited by 50 publications

(46 citation statements)

References 24 publications

(38 reference statements)

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“…MEK1 and MEK2 contribute to the divergent effects of ERK signaling, whereas MEK1-activated ERK2 induces cell proliferation, MEK2-activated ERK2 initiates growth arrest. [50][51][52] In our study, the HuR-MEK2 mRNA interaction, and MEK2 protein levels increased in ATM wild-type but not in ATM null cells after treatment with IR. These results support the importance of ATM/Chk2 signaling on the role of HuR in regulation of MEK2 levels and its contribution to IR-induced cell arrest, an attenuated cellular response in the absence of an ATM protein (in ATM null cells).…”

Section: Discussionsupporting

confidence: 44%

ATM regulates a DNA damage response posttranscriptional RNA operon in lymphocytes

Mazan-Mamczarz

Hagner

Zhang

et al. 2011

Blood

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Maintenance of genomic stability depends on the DNA damage response, a biologic barrier in early stages of cancer development. Failure of this response results in genomic instability and high predisposition toward lymphoma, as seen in patients with ataxia-telangiectasia mutated (ATM) dysfunction. ATM activates multiple cell-cycle checkpoints and DNA repair after DNA damage, but its influence on posttranscriptional gene expression has not been examined on a global level. We show that ionizing radiation modulates the dynamic association of the RNA-binding protein HuR with target mRNAs in an ATM-dependent manner, potentially coordinating the genotoxic response as an RNA operon. Pharmacologic ATM inhibition and use of ATM-null cells revealed a critical role for ATM in this process. Numerous mRNAs encoding cancer-related proteins were differentially associated with HuR depending on the functional state of ATM, in turn affecting expression of encoded proteins. The findings presented here reveal a previously unidentified role of ATM in controlling gene expression posttranscriptionally. Dysregulation of this DNA damage response RNA operon is probably relevant to lymphoma development in ataxia-telangiectasia persons. These novel RNA regulatory modules and genetic networks provide critical insight into the function of ATM in oncogenesis.

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Section: Discussionsupporting

confidence: 44%

ATM regulates a DNA damage response posttranscriptional RNA operon in lymphocytes

Mazan-Mamczarz

Hagner

Zhang

et al. 2011

Blood

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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.

166

158

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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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“…36 Furthermore, knockdown of KSR1 sensitized endometrial carcinoma cells to death receptor-mediated apoptosis. 37 Although deletion of Mek1 inhibits tumor formation in the skin, 38 it was shown that shRNA knockdown of Mek1 in murine hematopoietic stem cells facilitated Myc-induced tumor development. 39 However, the decrease in survival of the mice with Mek1 knockdown was not reported to be statistically significant, but may reflect different requirements of Mek1 signaling in stem cells.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Ras/Mapk pathway signaling inhibits Myc-induced lymphomagenesis

Gramling

Eischen

2012

Cell Death Differ

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Although the Myc transcription factor has been shown necessary for the oncogenic function of Ras, the contribution of Ras pathway signaling to the oncogenic function of Myc remains unresolved. We report the novel findings that Myc alone induced Ras/Mapk pathway signaling, and increased signaling following growth factor stimulation. Deletion of the scaffold protein kinase suppressor of Ras 1 (Ksr1) attenuated signaling through the Ras/Mapk pathway, including activation following Myc induction. B cells that lacked Ksr1 exhibited reduced proliferation and increased cytokine deprivation-induced apoptosis. Overexpression of Myc rescued the proliferation defect of Ksr1-null B cells, but loss of Ksr1 increased sensitivity of B cells to Myc-induced apoptosis. Notably, there was a significant delay in lymphoma development in Ksr1-null mice overexpressing Myc in B cells (El-myc transgenic mice). There was an elevated frequency of p53 inactivation, indicative of increased selective pressure to bypass the p53 tumor suppressor pathway, in Ksr1-null El-myc lymphomas. Therefore, loss of Ksr1 inhibits Ras/Mapk pathway signaling leading to increased Myc-induced B-cell apoptosis, and this results in reduced B-cell transformation and lymphoma development. The c-Myc transcription factor is an oncoprotein that is frequently overexpressed in hematological malignancies through translocations, amplifications, and other less characterized mechanisms. Overexpression of Myc, which drives cell cycle progression, is a well-characterized initiating step in human Burkitt's lymphoma, a non-Hodgkin's B-cell lymphoma. The role of Myc in non-Hodgkin's B-cell lymphoma was established in part by the Em-myc transgenic mouse model that overexpresses Myc in B-cells and develops pre-B/B-cell lymphoma. 1 Overexpression of Myc in primary B cells triggers activation of the Arf-Mdm2-p53 tumor suppressor pathway, which leads to apoptosis. Specifically, Myc induces Arf, which inhibits Mdm2, causing p53 activation and B-cell apoptosis. Myc-overexpressing B cells that acquire mutations that inhibit apoptosis survive and can be transformed. This is exemplified in that 80% of the lymphomas that arise in Em-myc mice have deleted Arf, overexpress Mdm2, or have mutated or deleted p53, all of which inhibit Myc-induced apoptosis. 2 Similar observations have been made in human lymphomas. [3][4][5] Therefore, whereas Myc overexpression induces B-cell transformation in vivo, it requires B cells to gain resistance to apoptosis induced by the hyperproliferative signals from Myc for this to occur.The Ras-Raf-Mek-Mapk/Erk (Ras/Mapk) signaling pathway is essential for cell growth, differentiation, and cell survival. 6 Kinase suppressor of Ras 1 (Ksr1) was first identified as a positive modulator of Ras signaling in genetic screens of Drosophila and C. elegans. 7 Subsequent studies have shown Ksr1 functions as a scaffold protein that can bind and facilitate signaling of multiple components of the Ras/Mapk signaling pathway. 6 Deletion of Ksr1 results in decreased Mapk-Erk1/2 ...

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Selective Role for Mek1 but not Mek2 in the Induction of Epidermal Neoplasia

Cited by 50 publications

References 24 publications

ATM regulates a DNA damage response posttranscriptional RNA operon in lymphocytes

ATM regulates a DNA damage response posttranscriptional RNA operon in lymphocytes

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

Suppression of Ras/Mapk pathway signaling inhibits Myc-induced lymphomagenesis

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