Prostaglandins differently regulate FGF-2 and FGF receptor expression and induce nuclear translocation in osteoblasts via MAPK kinase

Sabbieti, Maria Giovanna; Marchetti, Luigi; Gabrielli, María Gabriella; Menghi, Maura; Materazzi, Stefano; Menghi, G; Raisz, Lawrence G.; Hurley, Marja M.

doi:10.1007/s00441-004-0981-8

Cited by 42 publications

(39 citation statements)

References 42 publications

(36 reference statements)

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“…PR interacts with FGFR-2 and STAT5 in cells treated with FGF2 or with MPA pPR and pSTAT5 act as transcription factors (11,21) and FGFR-2 may be immunolocalized in the nuclei of ligandstimulated cells (3,23,24). FGF2 binds preferentially to FGFR-2 and it may also bind to other members of the FGFR family (25).…”

Section: Mpa and Fgf2 Induce Erk Akt And Stat5 Phosphorylationmentioning

confidence: 99%

Interaction between FGFR-2, STAT5, and Progesterone Receptors in Breast Cancer

et al. 2011

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Fibroblast growth factor (FGF) receptor 2 (FGFR-2) polymorphisms have been associated with an increase in estrogen receptor and progesterone receptor (PR)-positive breast cancer risk; however, a clear mechanistic association between FGFR-2 and steroid hormone receptors remains elusive. In previous works, we have shown a cross talk between FGF2 and progestins in mouse mammary carcinomas. To investigate the mechanisms underlying these interactions and to validate our findings in a human setting, we have used T47D human breast cancer cells and human cancer tissue samples. We showed that medroxyprogesterone acetate (MPA) and FGF2 induced cell proliferation and activation of ERK, AKT, and STAT5 in T47D and in murine C4-HI cells. Nuclear interaction between PR, FGFR-2, and STAT5 after MPA and FGF2 treatment was also showed by confocal microscopy and immunoprecipitation. This effect was associated with increased transcription of PRE and/or GAS reporter genes, and of PR/STAT5-regulated genes and proteins. Two antiprogestins and the FGFR inhibitor PD173074, specifically blocked the effects induced by FGF2 or MPA respectively. The presence of PR/FGFR-2/ STAT5 complexes bound to the PRE probe was corroborated by using NoShift transcription and chromatin immunoprecipitation of the MYC promoter. Additionally, we showed that T47D cells stably transfected with constitutively active FGFR-2 gave rise to invasive carcinomas when transplanted into NOD/SCID mice. Nuclear colocalization between PR and FGFR-2/STAT5 was also observed in human breast cancer tissues. This study represents the first demonstration of a nuclear interaction between FGFR-2 and STAT5, as PR coactivators at the DNA progesterone responsive elements, suggesting that FGFRs are valid therapeutic targets for human breast cancer treatment. Cancer Res; 71(10); 3720-31. Ó2011 AACR.

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Section: Mpa and Fgf2 Induce Erk Akt And Stat5 Phosphorylationmentioning

confidence: 99%

Interaction between FGFR-2, STAT5, and Progesterone Receptors in Breast Cancer

et al. 2011

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“…Nuclear accumulation of FGFR1, induced by the same surface receptors (recently nuclear accumulation was also shown to be induced by E-cadherin (25)), feeds the signal forward to CBP to facilitate gene activation, and enables activation of the CBP-regulated developmental gene programs. the developmental functions of nuclear FGFR2 (20,21) …”

Section: Discussionmentioning

confidence: 99%

“…Nuclear FGFR2 accumulation occurred in association with prostaglandin-induced osteoblast development (20) and in differentiating Sertoli cells (21). Like nuclear FGFR1 in NPCs, FGFR2 does not accumulate in the nuclei of proliferating Sertoli precursors but in cells that exit the cell cycle.…”

mentioning

confidence: 99%

Control of CREB-binding Protein Signaling by Nuclear Fibroblast Growth Factor Receptor-1

Fang

Stachowiak

Dunham-Ems

et al. 2005

Journal of Biological Chemistry

170

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In integrative nuclear fibroblast growth factor receptor-1 (FGFR1) signaling a newly synthesized FGFR1 translocates to the nucleus to stimulate cell differentiation and associated gene activities. The present study shows that FGFR1 accumulates and interacts with the transcriptional co-activator CREB-binding protein (CBP) in nuclear speckle domains in the developing brain and in neural progenitor-like cells in vitro, which accompanies differentiation and postmitotic growth. Cell differentiation and gene activation by nuclear FGFR1 do not require tyrosine kinase activity. Instead, FGFR1 stimulates transcription in cooperation with CBP by increasing recruitment of RNA polymerase II and histone acetylation at the active gene promoter. FGFR1 is a multifactorial protein whose N terminus interacts with CBP and C terminus with ribosomal S6 kinase 1 (RSK1). Nuclear FGFR1 augments CBP-mediated transcription by 1) releasing the CBP C-terminal domain from RSK1 inhibition and 2) activating the CBP N-terminal domain. The interaction of FGFR1 with CBP and RSK1 allows activation of gene transcription and may play a role in cell differentiation.During ontogeny, cells in the nervous system and in other tissues multiply, grow, and differentiate under the control of a plethora of extracellular signals. Progression through developmental phases requires concerted regulation of multiple genes, which occurs at the level of sequence specific transcription factors and at chromatin locations where remodeling occurs following histone modifications (1). Central characters in coordinating these events are transcription co-activators CREBbinding protein (CBP) 1 and its homolog p300. CBP and/or p300 function at the ends of several signaling cascades and interact with components of the basal transcription machinery. CBP/ p300 have intrinsic histone acetyltransferase activity and provide scaffolding for the multiprotein complexes that facilitate formation and stabilization of the RNA pol II holoenzyme complex and chromatin remodeling essential for initiation and continued transcription (2). CBP activity can be affected by phosphorylation with a variety of serine/threonine kinases (3, 4) as well as by methylation (5, 6). CBP functions are also influenced by cross-talk among distinct signaling cascades that compete for the limiting amounts of CBP (7-9). For instance, Ras-mediated mitogenic stimulation induces binding of CBP to serine/threonine ribosomal S6 kinase (pp90 RSK1), which phosphorylates and activates CREB and other sequence-specific transcription factors. Sequestering of CBP by RSK1 appears to channel the thrust of cell stimulation via the Ras pathway (i.e. mitogen activation of the c-fos gene) while blocking cAMP-mediated stimulation of the tyrosine hydroxylase gene (specific for differentiated catecholaminergic cells) (10). Hence, dynamic associations between CBP and RSK1 could allow CBP to activate distinct sets of genes and thereby promote different ontogenic phases. However, how the CBP-RSK interaction may be regulated by extracel...

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“…FGF2 is a potent mitogenic factor for several different cell types, including endothelial cells, and can induce angiogenesis by stimulating endothelial cell proliferation, migration, and expression of proteases, growth factors, and integrins involved in angiogenesis (26)(27)(28)(29). TGF-β has been shown to enhance production of FGF2 in osteoblasts and positively modulate osteoblast differentiation and bone formation (30)(31)(32). In aortic endothelial cells, TGF-β stimulation of a complex con-taining activin-like kinase receptor 5 (ALK5), TGF-β receptor II (TβRII), and SMAD2 enhances VEGF expression (33), but it is unclear whether there is similar activity at sites of bone remodeling.…”

Section: Bone Remodeling Dynamically Changes the Bone Marrow Microenvmentioning

confidence: 99%

Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling

Crane¹,

Cao²

2014

J. Clin. Invest.

363

300

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During bone resorption, abundant factors previously buried in the bone matrix are released into the bone marrow microenvironment, which results in recruitment and differentiation of bone marrow mesenchymal stem cells (MSCs) for subsequent bone formation, temporally and spatially coupling bone remodeling. Parathyroid hormone (PTH) orchestrates the signaling of many pathways that direct MSC fate. The spatiotemporal release and activation of matrix TGF-β during osteoclast bone resorption recruits MSCs to bone-resorptive sites. Dysregulation of TGF-β alters MSC fate, uncoupling bone remodeling and causing skeletal disorders. Modulation of TGF-β or PTH signaling may reestablish coupled bone remodeling and be a potential therapy. IntroductionIn humans, the skeleton undergoes continuous remodeling throughout adulthood. To maintain skeletal integrity, the activity of two cell types must be precisely coordinated. Osteoclasts, which resorb bone, are multinucleated cells derived from macrophages/monocytes in the HSC lineage. Osteoblasts, which deposit calcified bone matrix, are derived from bone marrow mesenchymal stem cells (MSCs; also referred to as bone marrow stromal cells or skeletal stem cells; ref. 1). The bone remodeling cycle is characterized by three distinct phases: (a) initiation, during which osteoclasts are formed and resorb damaged bone; (b) reversal, the transition of osteoclast to osteoblast activity; and (c) formation, when osteoblasts replace the portion of bone that was resorbed (2). Key steps in the reversal period include termination of osteoclast bone resorption and recruitment/differentiation of MSCs (2). Skeletal homeostasis is maintained by precise regulatory mechanisms during the reversal phase.The bone marrow microenvironment that is created during osteoclast bone resorption directs MSC fate. During osteoclastmediated bone resorption, multiple factors are released from the bone matrix and/or secreted locally, creating an osteogenic microenvironment that promotes MSC recruitment and osteoblast differentiation for new bone formation (3-6). Parathyroid hormone (PTH), the systemic hormone that regulates calcium homeostasis, plays a major role in orchestrating bone remodeling by modulating the bone marrow microenvironment and regulating osteogenic signaling pathways (7-16). Latent TGF-β1, which is abundant in the bone matrix, is released and activated by osteoclasts to specifically induce migration of MSCs to bone-resorptive sites (17)(18)(19). Because these two pathways have specific effects on MSC fate, their coordinated regulation is critical to bone remodeling.Here, we discuss the current understanding of how the bone marrow microenvironment at resorption sites affects MSCs and contributes to coupled bone remodeling. We specifically focus on how PTH regulates the osteogenic bone marrow microenvironment and how TGF-β promotes MSC recruitment. We also describe specific skeletal diseases that result from disruption of coupled bone remodeling. Finally, we address how modulation of TGF-β or PTH signal...

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Prostaglandins differently regulate FGF-2 and FGF receptor expression and induce nuclear translocation in osteoblasts via MAPK kinase

Cited by 42 publications

References 42 publications

Interaction between FGFR-2, STAT5, and Progesterone Receptors in Breast Cancer

Interaction between FGFR-2, STAT5, and Progesterone Receptors in Breast Cancer

Control of CREB-binding Protein Signaling by Nuclear Fibroblast Growth Factor Receptor-1

Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling

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