Dataset Information

Elucidating distinct roles for NF1 in melanomagenesis.

ABSTRACT: BRAF mutations play a well-established role in melanomagenesis; however, without additional genetic alterations, tumor development is restricted by oncogene-induced senescence (OIS). Here, we show that mutations in the NF1 tumor suppressor gene cooperate with BRAF mutations in melanomagenesis by preventing OIS. In a genetically engineered mouse model, Nf1 mutations suppress Braf-induced senescence, promote melanocyte hyperproliferation, and enhance melanoma development. Nf1 mutations function by deregulating both phosphoinositide 3-kinase and extracellular signal-regulated kinase pathways. As such, Nf1/Braf-mutant tumors are resistant to BRAF inhibitors but are sensitive to combined inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase and mTOR. Importantly, NF1 is mutated or suppressed in human melanomas that harbor concurrent BRAF mutations, NF1 ablation decreases the sensitivity of melanoma cell lines to BRAF inhibitors, and NF1 is lost in tumors from patients following treatment with these agents. Collectively, these studies provide mechanistic insight into how NF1 cooperates with BRAF mutations in melanoma and show that NF1/neurofibromin inactivation may have an impact on responses to targeted therapies.

SUBMITTER: Maertens O

PROVIDER: S-EPMC3595355 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Elucidating distinct roles for NF1 in melanomagenesis.

Maertens Ophélia O Johnson Bryan B Hollstein Pablo P Frederick Dennie T DT Cooper Zachary A ZA Messiaen Ludwine L Bronson Roderick T RT McMahon Martin M Granter Scott S Flaherty Keith K Wargo Jennifer A JA Marais Richard R Cichowski Karen K

Cancer discovery 20121121 3

BRAF mutations play a well-established role in melanomagenesis; however, without additional genetic alterations, tumor development is restricted by oncogene-induced senescence (OIS). Here, we show that mutations in the NF1 tumor suppressor gene cooperate with BRAF mutations in melanomagenesis by preventing OIS. In a genetically engineered mouse model, Nf1 mutations suppress Braf-induced senescence, promote melanocyte hyperproliferation, and enhance melanoma development. Nf1 mutations function by ...[more]

PMID: 23171796

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Project description:BACKGROUND:Supervisors play an essential role in implementation by diffusing and synthesizing information, selling implementation, and translating top management's project plans to frontline workers. Theory and emerging evidence suggest that through these roles, supervisors shape implementation climate-i.e., the degree to which innovations are expected, supported, and rewarded. However, it is unclear exactly how supervisors carry out each of these roles in ways that contribute to implementation climate-this represents a gap in the understanding of the causal mechanisms that link supervisors' behavior with implementation climate. This study examined how supervisors' performance of each of these roles influences three core implementation climate domains (expectations, supports, and rewards). MATERIALS AND METHODS:A sequenced behavioral health screening, assessment, and referral intervention was implemented within a county-based child welfare agency. We conducted 6 focus groups with supervisors and frontline workers from implementing work units 6 months post-implementation (n?=?51) and 1 year later (n?=?40) (12 groups total). Participants were asked about implementation determinants, including supervision and implementation context. We audio-recorded, transcribed, and analyzed focus groups using an open coding process during which the importance of the supervisors' roles emerged as a major theme. We further analyzed this code using concepts and definitions related to middle managers' roles and implementation climate. RESULTS:In this work setting, supervisors (1) diffused information about the intervention proactively, and in response to workers' questions, (2) synthesized information by tailoring it to workers' individual needs, (3) translated top managements' project plans into day-to-day tasks through close monitoring and reminders, and (4) justified implementation. All four of these roles appeared to shape the implementation climate by conveying strong expectations for implementation. Three roles (diffusing, synthesizing, and mediating) influenced climate by supporting workers during implementation. Only one role (diffusing) influenced climate by conveying rewards. CONCLUSIONS:Supervisors shaped implementation climate by carrying out four roles (diffusing, synthesizing, mediating, and selling). Findings suggest that the interaction of these roles convey expectations and support for implementation (two implementation climate domains). Our study advances the causal theory explaining how supervisors' behavior shapes the implementation climate, which can inform implementation practice.

Dataset Information

Elucidating distinct roles for NF1 in melanomagenesis.

Publications

Elucidating distinct roles for NF1 in melanomagenesis.

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