Mek1/2 gene dosage determines tissue response to oncogenic Ras signaling in the skin

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

doi:10.1038/onc.2008.459

Cited by 24 publications

(13 citation statements)

References 37 publications

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“…Most studies have focused on the role of ERKs, MEKs, and related kinases in protein phosphorylation and dephosphorylation or other feedback mechanisms in these pathways 24, However, our results in HMESO cells illustrate unique roles of ERK1 and ERK2 in gene transcription and function, revealing several ERK2-specific genes that may govern MM cell survival, inhibition of apoptosis, and essential processes (migration, invasion, angiogenesis) involved in the maintenance of tumor homeostasis. Data in Figure 4A showing that inhibition of ERK1 or ERK2 inhibits MM cell proliferation, support some reports suggesting that ERK1 and ERK2 (or MEK1 and MEK2) are interchangeable and functionally redundant, especially in the epidermis 25. However, blocking ERK2 selectively inhibited parameters of tumor function in vitro and growth of epithelioid MMs.…”

Section: Discussionsupporting

confidence: 84%

ERK2 is essential for the growth of human epithelioid malignant mesotheliomas

Shukla

Hillegass

MacPherson

et al. 2011

Intl Journal of Cancer

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Members of the extracellular signal-regulated kinase (ERK) family may have distinct roles in the development of cell injury and repair, differentiation and carcinogenesis. Here, we show, using a synthetic small-molecule MEK1/2 inhibitor (U0126) and RNA silencing of ERK1 and 2, comparatively, that ERK2 is critical to transformation and homeostasis of human epithelioid malignant mesotheliomas (MMs), asbestos-induced tumors with a poor prognosis. Although MM cell (HMESO) lines stably transfected with shERK1 or shERK2 both exhibited significant decreases in cell proliferation in vitro, injection of shERK2 cells, and not shERK1 cells, into immunocompromised severe combined immunodeficiency (SCID) mice showed significant attenuated tumor growth in comparison to shControl (shCon) cells. Inhibition of migration, invasion and colony formation occurred in shERK2 MM cells in vitro, suggesting multiple roles of ERK2 in neoplasia. Microarray and quantitative real-time PCR analyses revealed gene expression that was significantly increased (CASP1, TRAF1 and FAS) or decreased (SEMA3E, RPS6KA2, EGF and BCL2L1) in shERK2-transfected MM cells in contrast to shCon-transfected MM cells. Most striking decreases were observed in mRNA levels of Semaphorin 3 (SEMA3E), a candidate tumor suppressor gene linked to inhibition of angiogenesis. These studies demonstrate a key role of ERK2 in novel gene expression critical to the development of epithelioid MMs. After injection of sarcomatoid human MM (PPMMill) cells into SCID mice, both shERK1 and shERK2 lines showed significant decreased tumor growth, suggesting heterogeneous effects of ERKs in individual MMs.

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Section: Discussionsupporting

confidence: 84%

ERK2 is essential for the growth of human epithelioid malignant mesotheliomas

Shukla

Hillegass

MacPherson

et al. 2011

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Most studies have focused on the role of ERKs, MEKs and related kinases in protein phosphorylation and dephosphorylation or other feedback mechanisms in these pathways,24 However, our results in HMESO cells illustrate unique roles of ERK1 and ERK2 in gene transcription and function, revealing several ERK2‐specific genes that may govern MM cell survival, inhibition of apoptosis and essential processes (migration, invasion and angiogenesis) involved in the maintenance of tumor homeostasis. Data in Figure 4 a showing that inhibition of ERK1 or ERK2 inhibits MM cell proliferation support some reports suggesting that ERK1 and ERK2 (or MEK1 and MEK2) are interchangeable and functionally redundant, especially in the epidermis 25. However, blocking ERK2 selectively inhibited parameters of tumor function in vitro and growth of epithelioid MMs.…”

Section: Discussionsupporting

confidence: 81%

Neoadjuvant therapy is associated with improved survival in resectable pancreatic adenocarcinoma

Artinyan

Anaya

McKenzie

et al. 2010

Cancer

114

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A 1D Koch fractal electromagnetic bandgap (KFEBG) microstrip structure is proposed.It is conceived by replacing the conventional holes etched in the ground plane of a microstrip line by level‐1 Koch fractal cell geometries, which have been obtained from a hexagonal shape. In the case of the conventional 1D electromagnetic bandgap (EBG) microstrip structure with periodic hole pattern, the design is limited to r/a ratios lower than 0.45, whereas the proposed pattern allows achieving r/a ratios higher than 0.5. It is shown that the conventional EBG and KFEBG microstrip structures behave as a stopband filter as r/a < 0.45. However, for r/a = 0.55, the measurements have confirmed that the 1D KFEBG microstrip structure presents a ultra‐wide stopband and, therefore, the proposed structure with r/a > 0.5 can be useful for the design of low‐pass filters. © 2011 Wiley Periodicals, Inc. Microwave Opt Technol Lett 53:646–649, 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/mop.25763

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“…Similarly, we find in the present study that Mek1 and Mek2 knockout mice display equivalent levels of Erk1/2 phosphorylation upon DMBA/TPA treatment. Furthermore, in another study, we find that activation of oncogenic Ras in mouse skin containing only two of the four Mek1/2 alleles produces equivalent hyperplasia and Erk1/2 phosphorylation regardless of whether the remaining alleles are both Mek1 , both Mek2 , or one of each isoform (21). Together, these results suggest that differential expression of Mek- and Erk-interacting proteins, and not different levels of Erk1/2 phosphorylation, may underlie the difference in tumorigenesis in Mek1 and Mek2 knockout mice.…”

Section: Discussionmentioning

confidence: 72%

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

et al. 2009

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The Ras/Raf/Mek/Erk mitogen-activated protein kinase pathway regulates fundamental processes in normal and malignant cells, including proliferation, differentiation, and cell survival. Mutations in this pathway have been associated with carcinogenesis and developmental disorders, making Mek1 and Mek2 prime therapeutic targets. In this study, we examined the requirement for Mek1 and Mek2 in skin neoplasia using the two-step 7,12-dimethylbenz(a)anthraacene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) skin carcinogenesis model. Mice lacking epidermal Mek1 protein develop fewer papillomas than both wild-type and Mek2-null mice following DMBA/TPA treatment. Mek1 knockout mice had smaller papillomas, delayed tumor onset, and half the tumor burden of wild-type mice. Loss of one Mek1 allele, however, did not affect tumor development, indicating that one Mek1 allele is sufficient for normal papilloma formation. No difference in TPA-induced hyperproliferation, inflammation, or Erk activation was observed between wild-type, conditional Mek1 knockout, and Mek2-null mice, indicating that Mek1 findings were not due to a general failure of these processes. These data show that Mek1 is important for skin tumor development and that Mek2 cannot compensate for the loss of Mek1 function in this setting.

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Mek1/2 gene dosage determines tissue response to oncogenic Ras signaling in the skin

Cited by 24 publications

References 37 publications

ERK2 is essential for the growth of human epithelioid malignant mesotheliomas

ERK2 is essential for the growth of human epithelioid malignant mesotheliomas

Neoadjuvant therapy is associated with improved survival in resectable pancreatic adenocarcinoma

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

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