RSK Is a Principal Effector of the RAS-ERK Pathway for Eliciting a Coordinate Promotile/Invasive Gene Program and Phenotype in Epithelial Cells

Doehn, Ulrik; Hauge, Camilla; Frank, Scott R.; Jensen, Claus Munk; Duda, Katarzyna; Nielsen, Jan; Cohen, Michael S.; Johansen, Jens Vilstrup; Winther, Benny R.; Lund, Leif R.; Winther, Ole; Taunton, Jack; Hansen, Steen Ingemann; Frödin, Morten

doi:10.1016/j.molcel.2009.08.002

Cited by 198 publications

(227 citation statements)

References 43 publications

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“…In A549 cells, FRA-1 overexpression induces in vitro invasion and anchorage-independent growth, along with in vivo metastasis (39). More recently, FRA-1 has been implicated in the control of EMT in response to the RAS-MEK-ERK pathway in multiple tumor cell systems (40)(41)(42)(43). Interactions between SMAD3/4 and AP-1 components are well-characterized examples of cooperation between transcription factors (44).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β–SMAD3 pathway in non-small cell lung adenocarcinoma

Risolino

Mandia

Iavarone

et al. 2014

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

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Pre-B-cell leukemia homeobox (Pbx)-regulating protein-1 (Prep1) is a ubiquitous homeoprotein involved in early development, genomic stability, insulin sensitivity, and hematopoiesis. Previously we have shown that Prep1 is a haploinsufficient tumor suppressor that inhibits neoplastic transformation by competing with myeloid ecotropic integration site 1 for binding to the common heterodimeric partner Pbx1. Epithelial-mesenchymal transition (EMT) is controlled by complex networks of proinvasive transcription factors responsive to paracrine factors such as TGF-β. Here we show that, in addition to inhibiting primary tumor growth, PREP1 is a novel EMT inducer and prometastatic transcription factor. In human non-small cell lung cancer (NSCLC) cells, PREP1 overexpression is sufficient to trigger EMT, whereas PREP1 down-regulation inhibits the induction of EMT in response to TGF-β. PREP1 modulates the cellular sensitivity to TGF-β by inducing the small mothers against decapentaplegic homolog 3 (SMAD3) nuclear translocation through mechanisms dependent, at least in part, on PREP1-mediated transactivation of a regulatory element in the SMAD3 first intron. Along with the stabilization and accumulation of PBX1, PREP1 induces the expression of multiple activator protein 1 components including the proinvasive Fos-related antigen 1 (FRA-1) oncoprotein. Both FRA-1 and PBX1 are required for the mesenchymal changes triggered by PREP1 in lung tumor cells. Finally, we show that the PREP1-induced mesenchymal transformation correlates with significantly increased lung colonization by cells overexpressing PREP1. Accordingly, we have detected PREP1 accumulation in a large number of human brain metastases of various solid tumors, including NSCLC. These findings point to a novel role of the PREP1 homeoprotein in the control of the TGF-β pathway, EMT, and metastasis in NSCLC.TALE proteins | PTGFβ P REP1 [pre-B-cell leukemia homeobox (Pbx)-regulating protein-1], also known as "PKNOX1" (PBX/knotted homeobox 1), belongs to the TALE (three-amino acid-loop-extension) family of homeodomain transcription factors, along with myeloid ecotropic integration site (MEIS) and PBX proteins. As indicated by its name, PREP1 retains PBX1 in the nucleus and induces its binding to DNA (1).PREP1 is essential in embryonic development. Although Prep1-null embryos die before gastrulation from apoptosis of the epiblast (2), hypomorphic Prep1-mutant mice (Prep i/i ), expressing severely decreased Prep1 levels (3-10% of wild-type) exhibit incompletely penetrant embryonic phenotypes, mainly characterized by alterations in hematopoiesis and angiogenesis (3).Prep1 deficiency affects cell proliferation and survival in various biological contexts. Decreased Prep1 expression results in increased apoptosis in Prep1 i/i embryos and mouse embryonic fibroblasts (MEFs) (4). In Prep1 −/− embryos, early preimplantation lethality is consequent to increased apoptosis in mouse pluripotent epiblast cells. Genetic analysis suggests that the lack of Prep1 confers increased sensitivity...

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Section: Discussionmentioning

confidence: 99%

Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β–SMAD3 pathway in non-small cell lung adenocarcinoma

Risolino

Mandia

Iavarone

et al. 2014

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

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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%

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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“…Fos‐related antigen 1 plays an important role in the formation of AP‐1 complexes, which regulate the expression of specific genes such as MMP‐1 8, 10. Protein stability is a major regulatory outcome of FRA1 protein expression, and extracellular signal‐regulated kinase (ERK)1/2 signalling is an important mediator of FRA1 protein stability 7.…”

Section: Introductionmentioning

confidence: 99%

Naringenin targets ERK2 and suppresses UVB‐induced photoaging

Jung

et al. 2016

J Cellular Molecular Medi

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A number of natural phytochemicals have anti‐photoaging properties that appear to be mediated through the inhibition of matrix metalloproteinase‐1 (MMP‐1) expression, but their direct target molecule(s) and mechanism(s) remain unclear. We investigated the effect of naringenin, a major flavonoid found in citrus, on UVB‐induced MMP‐1 expression and identified its direct target. The HaCaT human skin keratinocyte cell line and 3‐dimensional (3‐D) human skin equivalent cultures were treated or not treated with naringenin for 1 hr before exposure to UVB. The mechanism and target(s) of naringenin were analysed by kinase assay and multiplex molecular assays. Dorsal skins of hairless mice were exposed to UVB 3 times per week, with a dose of irradiation that was increased weekly by 1 minimal erythema dose (MED; 45 mJ/cm2) to 4 MED over 15 weeks. Wrinkle formation, water loss and water content were then assessed. Naringenin suppressed UVB‐induced MMP‐1 expression and AP‐1 activity, and strongly suppressed UVB‐induced phosphorylation of Fos‐related antigen (FRA)‐1 at Ser265. Importantly, UVB irradiation‐induced FRA1 protein stability was reduced by treatment with naringenin, as well as with a mitogen‐activated protein kinase (MEK) inhibitor. Naringenin significantly suppressed UVB‐induced extracellular signal‐regulated kinase 2 (ERK2) activity and subsequently attenuated UVB‐induced phosphorylation of p90RSK by competitively binding with ATP. Constitutively active MEK (CA‐MEK) increased FRA1 phosphorylation and expression and also induced MMP‐1 expression, whereas dominant‐negative ERK2 (DN‐ERK2) had opposite effects. U0126, a MEK inhibitor, also decreased FRA1 phosphorylation and expression as well as MMP‐1 expression. The photoaging data obtained from mice clearly demonstrated that naringenin significantly inhibited UVB‐induced wrinkle formation, trans‐epidermal water loss and MMP‐13 expression. Naringenin exerts potent anti‐photoaging effects by suppressing ERK2 activity and decreasing FRA1 stability, followed by down‐regulation of AP‐1 transactivation and MMP‐1 expression.

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RSK Is a Principal Effector of the RAS-ERK Pathway for Eliciting a Coordinate Promotile/Invasive Gene Program and Phenotype in Epithelial Cells

Cited by 198 publications

References 43 publications

Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β–SMAD3 pathway in non-small cell lung adenocarcinoma

Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β–SMAD3 pathway in non-small cell lung adenocarcinoma

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

Naringenin targets ERK2 and suppresses UVB‐induced photoaging

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