Extracellular Signal-Regulated Kinase 2 Interacts with and Is Negatively Regulated by the LIM-Only Protein FHL2 in Cardiomyocytes

Purcell, Nicole H.; Darwis, Dina; Bueno, Orlando F.; Müller, Judith; Schüle, Roland; Molkentin, Jeffery D.

doi:10.1128/mcb.24.3.1081-1095.2004

Cited by 139 publications

(163 citation statements)

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“…This cellular localization and/or expression of FHL2 in these cell lines have been shown to be highly regulated and might be an essential parameter in modulating different cellular functions. Notably, signals, as different as mitogenic restimulation of arrested cells, morphogenic stimulation or cell irradiation, strongly increase FHL2 expression and/or nuclear localization (Muller et al, 2002;Morlon and Sassone-Corsi, 2003;Philippar et al, 2004;Purcell et al, 2004). Consistent with this observation, the FHL2 gene was shown to be a direct target of both p53 (Scholl et al, 2000) and SRF (Philippar et al, 2004).…”

Section: Lim-only Protein Fhl2 Is a Negative Regulator Of E4f1supporting

confidence: 54%

“…Thus, upon ectopic expression in reporter assays, FHL2 behaves as a coactivator for several transcription factors, including AP-1 (Morlon and Sassone-Corsi, 2003), CREB (Fimia et al, 2000), androgen receptor (Muller et al, 2000), NF-kB (Stilo et al, 2002), WT1 (Du et al, 2002) and as a corepressor for the Promyelocytic leukemia zinc-finger protein (PLZF) (McLoughlin et al, 2002). Interestingly, DRAL/FHL2 was also described to directly associates with proteins involved in signal transduction, such as IGFBP-5 (Amaar et al, 2002), b-catenin (Martin et al, 2002;Wei et al, 2003;Labalette et al, 2004), a-and bintegrins (Wixler et al, 2000) and the map kinase erk2 (Purcell et al, 2004), suggesting that it might function as a molecular transmitter linking various signaling pathways to transcriptional regulation. Consistent with this scenario, DRAL/FHL2 cellular localization seems to be both nuclear and non-nuclear (Scholl et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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The LIM-only protein FHL2 is a negative regulator of E4F1

et al. 2006

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The E1A-targeted transcription factor E4F1 is a key player in the control of mammalian embryonic and somatic cell proliferation and survival. Mouse embryos lacking E4F die at an early developmental stage, whereas enforced expression of E4F1 in various cell lines inhibits cell cycle progression. E4F1-antiproliferative effects have been shown to depend on its capacity to repress transcription and to interact with pRb and p53. Here we show that full-length E4F1 protein (p120 E4F1 ) but not its E1A-activated and truncated form (p50 E4F1 ), interacts directly in vitro and in vivo with the LIM-only protein FHL2, the product of the p53-responsive gene FHL2/ DRAL (downregulated in rhabdomyosarcoma Lim protein). This E4F1-FHL2 association occurs in the nuclear compartment and inhibits the capacity of E4F1 to block cell proliferation. Consistent with this effect, ectopic expression of FHL2 inhibits E4F1 repressive effects on transcription and correlates with a reduction of nuclear E4F1-p53 complexes. Overall, these results suggest that FHL2/DRAL is an inhibitor of E4F1 activity. Finally, we show that endogenous E4F1-FHL2 complexes form in U2OS cells upon UV-light-induced nuclear accumulation of FHL2.

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Section: Lim-only Protein Fhl2 Is a Negative Regulator Of E4f1supporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

The LIM-only protein FHL2 is a negative regulator of E4F1

et al. 2006

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“…10 Secondly, FHL2 interacts with phosphorylated ERK2 in cardiomyocytes. 30 To test whether FHL2 is involved in MAPK-mediated regulation of AP1 transcription, we transfected the MDA-MB 231 shFHL2 and shSCR cells, respectively, with an AP1-dependent luciferase reporter gene (pAP1-Luc), and activated both ERK and JNK MAPKs by cotransfecting along with the reporter gene construct a constitutively active MAP kinase kinase (pFC-MEKK1). Being overexpressed this kinase is known to efficiently induce c-jun dependent transcription by activating both ERK1/2 and JNKs, which in turn phosphorylate and activate c-jun.…”

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

“…As a result, FHL2 inhibited the ability of activated ERK2 to reside within the nucleus, thereby inhibiting ERK-dependent transcriptional responses. 30 In women, breast cancer is the most incident form of cancer (275,100 cases) and the leading cause of death (88,400) in the European Union. 31 Up to date, little is known about interacting proteins and the function of FHL2 in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

Martin¹,

Kleiber²,

Wixler³

et al. 2007

Cell Cycle

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© 2 0 0 7 L A N D E S B I O S C I E N C E . D O N O T D I S T R I B U T E .[Cell Cycle 6:14, 1779-1788, 15 ABSTRAcTThe transcriptional cofactor FHL2 interacts with a broad variety of transcription factors and its expression is often deregulated in various types of cancer. Here we analyzed for the first time the molecular function of FHL2 in breast cancer. FHL2 is overexpressed in almost all human mammary carcinoma samples tested but not in normal breast tissues and only low levels of FHL2 expression were present in four premalignant ductal carcinoma in situ (DCIS). Cell cycle analysis revealed an upregulation of endogenous FHL2 towards G 2 /M in MDA-MB 231 cells and an accelerated G 2 /M transition when FHL2 expression was suppressed in these cells. In search for G 2 /M specific target genes regulated by FHL2, we found that expression of the cell cycle inhibitor p21 Cip1/Waf1 (hereafter p21) is dependent on FHL2 in MDA-MB 231 breast cancer cells. Downregulation of FHL2 by shRNA abrogated the cell cycle dependent upregulation of p21 as well as the induction of p21 in response to treatment with the DNA damaging agent doxorubicin. FHL2-dependent p21 expression occurs in a p53-independent manner and p21 expression can be downregulated by specific inhibition of mitogen-activated protein kinases (MAPKs), implicating an involvement of MAPK signaling in this regulation. Analysis of FHL2 contribution to the MAPK signaling identified FHL2 as an important downstream effector of MAPKs in breast cancer cells, capable of transactivating endogenous AP1 target genes as well as AP1 dependent reporter genes. Finally, downregulation of FHL2 reduces the ability of MDA-MB 231 cells to form colonies in soft agar, while FHL2 overexpression enhances colony formation of breast cancer cells. Thus, our findings indicate that overexpression of the transcriptional cofactor FHL2 contributes to breast cancer development by mediating transcriptional activation of MAPK target genes known to be involved in cancer progression, such as p21.

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“…(12,13) In addition, FHL2 is also shown to bind activated extracellular signal-regulated kinase 2 (ERK2) and prevents its translocation into nuclei in cardiomyocytes. (14) Despite this inhibitory activity, FHL2 is found to translocate from cytosol to nuclei in a Rho GTPase-dependent manner. (15) In the nuclei, FHL2 functions as a co-activator for many transcription factors including activator protein 1 (AP-1), cAMPresponsive element binding protein (CREB), androgen receptor, and ␤-catenin, which results in modulation of gene expression and cell differentiation.…”

mentioning

confidence: 99%

Four and Half Lim Protein 2 (FHL2) Stimulates Osteoblast Differentiation

Lai

Bai

Uthgenannt

et al. 2006

Journal of Bone and Mineral Research

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FHL2, a molecule that interacts with many integrins and transcription factors, was found to play an important role in osteoblast differentiation. Overexpression of FHL2 increases the accumulation of osteoblast differentiation markers and matrix mineralization, whereas FHL2 deficiency results in inhibition of osteoblast differentiation and decreased bone formation.Introduction: Integrin-matrix interaction plays a critical role in osteoblast function. It has been shown that the cytoplasmic domains of integrin ␤ subunits mediate signal transduction induced by integrin-matrix interaction. We reasoned that the identification of proteins interacting with ␤-cytoplasmic tails followed by analysis of the function of these proteins would enhance our understanding on integrin signaling and the roles of these proteins in osteoblast activities. Materials and Methods: Yeast two hybrid assay was used to identify proteins interacting with the cytoplasmic domain of integrin ␤5 subunit. The association of these proteins with integrin ␣v␤5 was confirmed by confocal analysis and co-immunoprecipitation. A stable MC3T3-E1 cells line overexpressing Four and Half Lim Protein 2 (FHL2) and mouse osteoblasts deficient in FHL2 were used to study the roles of FHL2 in osteoblast differentiation and bone formation. Matrix protein expression was determined by mRNA analysis and Western blotting. Matrix mineralization was detected by Alizarin red staining. Alkaline phosphatase activity was also measured. CT was used to determine bone histomorphometry. Results and Conclusions: FHL2 and actin-binding proteins, palladin and filamin A, were identified as proteins interacting with ␤5 cytoplasmic domain. FHL2 co-localized with ␣v␤5 at the focal adhesion sites in association with palladin and filamin A. FHL2 was also present in nuclei. Osteoblasts overexpressing FHL2 exhibited increased adhesion to and migration on matrix proteins. Conversely, FHL2 stimulation of CREB activity was dependent on integrin function because it was inhibited by Gly-Arg-Gly-Asp-Ser (GRGDS) peptide. The expression of osteoblast differentiation markers and Msx2 was upregulated, and bone matrix mineralization was increased in FHL2 overexpressing cells. In contrast, FHL2-deficient bone marrow cells and osteoblasts displayed decreased osteoblast colony formation and differentiation, respectively, compared with wildtype cells. Moreover, FHL2-deficient female mice exhibited greater bone loss than the wildtype littermates after ovariectomy. Thus, FHL2 plays an important role in osteoblast differentiation and bone formation.

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Extracellular Signal-Regulated Kinase 2 Interacts with and Is Negatively Regulated by the LIM-Only Protein FHL2 in Cardiomyocytes

Cited by 139 publications

References 43 publications

The LIM-only protein FHL2 is a negative regulator of E4F1

The LIM-only protein FHL2 is a negative regulator of E4F1

FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

Four and Half Lim Protein 2 (FHL2) Stimulates Osteoblast Differentiation

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