The role of proto-oncogene Fra-1 in remodeling the tumor microenvironment in support of breast tumor cell invasion and progression

Luo, Yunping; Zhou, He; Krueger, Joerg; Kaplan, Charles D.; Liao, Daiqing; Markowitz, Dorothy; Liu, Cheng; Chen, Tingmei; Chuang, Tsung‐Hsien; Xiang, Rong; Reisfeld, Ralph A.

doi:10.1038/onc.2009.308

Cited by 80 publications

(74 citation statements)

References 36 publications

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“…Overexpression of the Fra-1 transcription factor in human cancers is strongly linked to tumour growth, migration and invasion Belguise et al, 2005;Debinski and Gibo, 2005;Pollock et al, 2005;Young and Colburn, 2006;Adiseshaiah et al, 2007;Doehn et al, 2009;Luo et al, 2010). Understanding the mechanisms regulating Fra-1 accumulation in tumour cells is a key issue, but one that is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…The Fos-related antigen-1 (Fra-1) is a Fos family member that is persistently overexpressed in a variety of cancers and tumour cell lines, where it has been reported to regulate cell proliferation, survival, migration and invasion Belguise et al, 2005;Debinski and Gibo, 2005;Pollock et al, 2005;Kakumoto et al, 2006;Young and Colburn, 2006;Adiseshaiah et al, 2007;Casalino et al, 2007;Doehn et al, 2009;Luo et al, 2010). A number of Fra-1-regulated genes have been implicated in these processes, including modulators of cell cycle progression (CCND1 and CCNA2; Burch et al, 2004;Casalino et al, 2007;Vikhanskaya et al, 2007), epithelial-mesenchymal transitions (ZEB1 and ZEB2; Shin et al, 2010, extracellular matrix degradation (MMP1 and MMP9;Kustikova et al, 1998) and migration (cd44, VEGF, c-met; Ramos-Nino et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

et al. 2011

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Fos-related antigen-1 (Fra-1) is a member of the Activator Protein-1 (AP-1) transcription factor superfamily that is overexpressed in a variety of cancers, including colon, breast, lung, bladder and brain. High Fra-1 levels are associated with enhanced cell proliferation, survival, migration and invasion. Despite its frequent overexpression, the molecular mechanisms that regulate the accumulation of Fra-1 proteins in tumour cells are not well understood. Here, we show that turnover of Fra-1, which does not require ubiquitylation, is cooperatively regulated by two distinct mechanisms-association with the 19S proteasomal subunit, TBP-1, and by a C-terminal degron, which acts independently of TBP-1, but is regulated by RAS-ERK (extracellular signal-regulated kinase) signalling. TBP-1 depletion stabilized Fra-1 and further increased its levels in tumour cells expressing RAS-ERK pathway oncogenes. These effects correlated with increased AP-1 transcriptional activity. We suggest that during Fra-1 degradation, association with TBP-1 provides a mechanism for ubiquitin-independent proteasomal recognition, while the C terminus of the protein regulates its subsequent proteolytic processing.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

et al. 2011

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“…Fra-1 is known to alter tumor-associated macrophage polarization (47,48). Thus, we studied whether Fra-1 affects macrophage polarization after CS exposure.…”

Section: D/dmentioning

confidence: 99%

Myeloid-Specific Fos-Related Antigen-1 Regulates Cigarette Smoke–Induced Lung Inflammation, Not Emphysema, in Mice

Vaz

Rajasekaran

Potteti

et al. 2015

Am J Respir Cell Mol Biol

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Heightened lung inflammation is a cardinal feature of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS)-induced macrophage recruitment and activation, accompanied by abnormal secretion of a number of inflammatory cytokines and matrix metalloproteinases, play a major role in the pathophysiology of COPD. The Fos-related antigen-1 (Fra-1) transcription factor differentially regulates several cellular processes that are implicated in COPD, such as inflammation and immune responses, cell proliferation and death, and extracellular remodeling. Although CS stimulates Fra-1 expression in the lung, the precise role of this transcription factor in the regulation of CS-induced lung inflammation in vivo is poorly understood. Here, we report that myeloid-specific Fra-1 signaling is important for CS-induced lung macrophagic inflammatory response. In response to chronic CS exposure, mice with Fra-1 specifically deleted in myeloid cells showed reduced levels of CS-induced lung macrophagic inflammation, accompanied by decreased expression levels of proinflammatory cytokines compared with their wild-type counterparts. Consistent with this result, bone marrow-derived Fra-1-null macrophages treated with CS showed decreased levels of proinflammatory mediators and matrix metalloproteinases. Interestingly, deletion of Fra-1 in myeloid cells did not affect the severity of emphysema. We propose that Fra-1 plays a key role in promoting chronic CS-induced lung macrophagic inflammation in vivo, and that targeting this transcription factor may be useful in dampening persistent lung inflammation in patients with COPD.Keywords: emphysema; inflammation; activator protein-1; lung; macrophages Clinical RelevancePersistent macrophagic inflammation in the smoker's lung has been implicated in the development and perpetuation of chronic obstructive pulmonary disease (COPD). Here, we demonstrate, using a tissue-specific knockout model, that Fosrelated antigen-1 (Fra-1) transcription factor signaling in myeloid cells plays a key role in promoting chronic cigarette smoke-induced lung macrophagic inflammation in vivo. Thus, either depletion or inhibition of Fra-1 activity may be useful in dampening lung inflammation in patients with COPD.Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of chronic morbidity and mortality in the United States, and is projected to rank fifth in 2020 in burden of disease worldwide. The disease is characterized by chronic inflammation of peripheral and central airways, increased thickness of airway walls, and destruction of alveolar septa, ultimately leading to the destruction of the alveolar walls (1). Although cigarette smoking is a major risk factor for COPD, the exact mechanism(s) underlying cigarette smoke (CS)-induced lung inflammation and emphysema is not yet fully understood and Author Contributions: M.V. and S.P.R. were involved in the conception, delineation of hypotheses, and design of the study, as well as the analysis and interpretation of data; M.V. performed in v...

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“…Fos family transcription factors are conserved regulators of invasion and have been implicated in regulating a battery of genes that contribute to basement membrane breaching (Luo et al, 2010;Matus et al, 2010;Milde-Langosch, 2005;Ozanne et al, 2007;Sherwood et al, 2005;Uhlirova and Bohmann, 2006;Young and Colburn, 2006). Several FOS-1A targets in the AC have been identified, including the extracellular matrix protein hemicentin, which is deposited in the basement membrane prior to invasion.…”

Section: Mig-10b Is a Target Of Fos-1a Regulation In The Acmentioning

confidence: 99%

MIG-10 (lamellipodin) has netrin-independent functions and is a FOS-1A transcriptional target during anchor cell invasion in C. elegans

2014

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To transmigrate basement membrane, cells must coordinate distinct signaling activities to breach and pass through this dense extracellular matrix barrier. Netrin expression and activity are strongly associated with invasion in developmental and pathological processes, but how netrin signaling is coordinated with other pathways during invasion is poorly understood. Using the model of anchor cell (AC) invasion in C. elegans, we have previously shown that the integrin receptor heterodimer INA-1/PAT-3 promotes netrin receptor UNC-40 (DCC) localization to the invasive cell membrane of the AC. UNC-6 (netrin)/UNC-40 interactions generate an invasive protrusion that crosses the basement membrane. To understand how UNC-40 signals during invasion, we have used genetic, site of action and live-cell imaging studies to examine the roles of known effectors of UNC-40 signaling in axon outgrowth during AC invasion. UNC-34 (Ena/VASP), the Rac GTPases MIG-2 and CED-10 and the actin binding protein UNC-115 (abLIM) are dedicated UNC-40 effectors that are recruited to the invasive membrane by UNC-40 and generate F-actin. MIG-10 (lamellipodin), an effector of UNC-40 in neurons, however, has independent functions from UNC-6/UNC-40. Furthermore, unlike other UNC-40 effectors, its expression is regulated by FOS-1A, a transcription factor that promotes basement membrane breaching. Similar to UNC-40, however, MIG-10 localization to the invasive cell membrane is also dependent on the integrin INA-1/PAT-3. These studies indicate that MIG-10 has distinct functions from UNC-40 signaling in cell invasion, and demonstrate that integrin coordinates invasion by localizing these molecules to the cell-basement membrane interface.

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The role of proto-oncogene Fra-1 in remodeling the tumor microenvironment in support of breast tumor cell invasion and progression

Cited by 80 publications

References 36 publications

A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

Myeloid-Specific Fos-Related Antigen-1 Regulates Cigarette Smoke–Induced Lung Inflammation, Not Emphysema, in Mice

MIG-10 (lamellipodin) has netrin-independent functions and is a FOS-1A transcriptional target during anchor cell invasion in C. elegans

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