A GR-motif functions in nuclear accumulation of the large FGF-2 isoforms and interferes with mitogenic signalling

Dono, Rosanna; James, Dominic I.; Zeller, Rolf

doi:10.1038/sj.onc.1201746

Cited by 32 publications

(25 citation statements)

References 30 publications

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“…Different FGF-2 isoforms have been overexpressed in both transgenic mice (Davis et al, 1997) and various normal and transformed cell lines (Pasumarthi et al, 1994(Pasumarthi et al, , 1996Joy et al, 1997;Dono et al, 1998;Grothe et al,1998). The resulting phenotypes support the proposition of FGF-2 isoform-specific functions.…”

Section: Introductionmentioning

confidence: 86%

Nuclear Activities of Basic Fibroblast Growth Factor: Potentiation of Low-Serum Growth Mediated by Natural or Chimeric Nuclear Localization Signals

Arese

Chen²,

Florkiewicz

et al. 1999

MBoC

115

106

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Human basic fibroblast growth factor (FGF-2) occurs in four isoforms: a low molecular weight (LMW FGF-2, 18 kDa) and three high molecular weight (HMW FGF-2, 22, 22.5, and 24 kDa) forms. LMW FGF-2 is primarily cytoplasmic and functions in an autocrine manner, whereas HMW FGF-2s are nuclear and exert activities through an intracrine, perhaps nuclear, pathway. Selective overexpression of HMW FGF-2 forms in fibroblasts promotes growth in low serum, whereas overexpression of LMW FGF-2 does not. The HMW FGF-2 forms have two functional domains: an amino-terminal extension and a common 18-kDa amino acid sequence. To investigate the role of these regions in the intracrine signaling of HMW FGF-2, we produced stable transfectants of NIH 3T3 fibroblasts overexpressing either individual HMW FGF-2 forms or artificially nucleartargeted LMW FGF-2. All of these forms of FGF-2 localize to the nucleus/nucleolus and induce growth in low serum. The nuclear forms of FGF-2 trigger a mitogenic stimulus under serum starvation conditions and do not specifically protect the cells from apoptosis. These data indicate the existence of a specific role for nuclear FGF-2 and suggest that LMW FGF-2 represents the biological messenger in both the autocrine/paracrine and intracrine FGF-2 pathways. INTRODUCTIONBasic fibroblast growth factor (FGF-2) 1 is a member of a large family of heparin-binding growth factors. Thus far 19 members (Nishimura et al., 1999) have been described. These proteins affect various biological processes ranging from cell proliferation to plasminogen activation, integrin expression, cell migration, embryonic development, and cell differentiation. FGFs also may be involved in tumor angiogenesis and malignant transformation (Burgess and Maciag, 1989;Rifkin and Moscatelli, 1989;Basilico and Moscatelli, 1992;Mason, 1994).The biological functions of the FGFs are mediated by their interaction with both high-and low-affinity plasma membrane receptors (Baird, 1994). A family consisting of four high-affinity tyrosine kinase FGFreceptors has been identified (Basilico and Moscatelli, 1992;Jaye et al., 1992). The interaction of FGF-2 with its plasma membrane high-affinity receptors induces autophosphorylation of the receptor and initiates the phosphorylation of tyrosine residues in cytosolic substrates (Fantl et al., 1993). The low-affinity receptors consist of heparan sulfate proteoglycans and are thought to provide a mechanism both to concentrate ligand and to present FGF dimers to tyrosine kinase receptors Baird, 1994) The prototypic members of the FGF family, FGF-1 and -2, lack a signal sequence for secretion, although the proteins are released and have been visualized in ‡ Corresponding author. E-mail address: aresem01@mcrcr.med. nyu.edu. 1 Abbreviations used: FGF-2, basic fibroblast growth factor; HMW FGF-2, high molecular weight FGF-2; LMW FGF-2, low molecular weight FGF-2.© 1999 by The American Society for Cell Biology 1429 the ECM of different tissues (Abraham et al., 1986;Jaye et al., 1986). The mechanism of FGF-1 and FGF-2 r...

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Section: Introductionmentioning

confidence: 86%

Nuclear Activities of Basic Fibroblast Growth Factor: Potentiation of Low-Serum Growth Mediated by Natural or Chimeric Nuclear Localization Signals

Arese

Chen²,

Florkiewicz

et al. 1999

MBoC

115

106

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“…The mechanism for nuclear targeting involves nuclear localization sequences embedded in the protein. These nuclear localization sequences typically consist of mono-or bi-partite basic residues, usually lysines and arginines or glycine-arginine repeats (Dono et al, 1998;Hock et al, 1998;Lu et al, 1998). Nuclear localization sequences are recognized by a class of proteins known as importins that bind these sequences and facilitate transport of the target protein to the nucleus.…”

Section: A 1 -Adrenergic Receptors In the Nuclei In Cardiac Myocytesmentioning

confidence: 99%

Cardiac Alpha₁-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

et al. 2013

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“…Most of non-classical types of NLSs consist of a single long stretch of non-basic aa (20-40 aa) as in hnRNP [12,13], HuR [14], IκBα [15] and Nab2p [16]. Some non-classical NLSs are a single short stretch containing one or more basic aa, but is distinct from the mNLS, as in Cdc6 [17], FGF2 [18], Mat2a [19,20] and Sam68 [21]. NES sequences are short hydrophobic sequences rich in leucines and/or isoleucines with a consensus sequence of L/Ix (1)(2)(3) Lx (2)(3)(4) LxL [22].…”

Section: Introductionmentioning

confidence: 99%

A unique sequence in the N-terminal regulatory region controls the nuclear localization of KLF8 by cooperating with the C-terminal zinc-fingers

Mehta

Wang

et al. 2009

Cell Res

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Krüppel-like factor 8 (KLF8) transcription factor plays a critical role in cell cycle progression, oncogenic transformation, epithelial to mesenchymal transition and invasion. However, its nuclear localization signal(s) (NLS) has not been identified. KLF8 shares with other KLFs monopartite NLSs (mNLS) and C 2 H 2 zinc fingers (ZFs), both of which have been shown to be the NLSs for some other KLFs. In this report, using PCR-directed mutagenesis and immunofluorescent microscopy, we show that disruption of the mNLSs, deletion of any single ZF, or mutation of the Zn 2+ -binding or DNA-contacting motifs did not affect the nuclear localization of KLF8. Deletion of >1.5 ZFs from Cterminus, however, caused cytoplasmic accumulation of KLF8. Surprisingly, deletion of amino acid (aa) 151-200 region almost eliminated KLF8 from the nucleus. S165A, K171E or K171R mutation, or treatment with PKC inhibitor led to partial cytoplasmic accumulation. Co-immunoprecipitation demonstrated that KLF8 interacted with importin-β and this interaction required the ZF motif. Deletion of aa 1-150 or 201-261 region alone did not alter the nuclear localization. BrdU incorporation and cyclin D1 promoter luciferase assays showed that the KLF8 mutants defective in nuclear localization could not promote DNA synthesis or cyclin D1 promoter activation as the wild-type KLF8 did. Taken together, these results suggest that KLF8 has two NLSs, one surrounding S165 and K171 and the other being two tandem ZFs, which are critical for the regulation of KLF8 nuclear localization and its cellular functions.

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A GR-motif functions in nuclear accumulation of the large FGF-2 isoforms and interferes with mitogenic signalling

Cited by 32 publications

References 30 publications

Nuclear Activities of Basic Fibroblast Growth Factor: Potentiation of Low-Serum Growth Mediated by Natural or Chimeric Nuclear Localization Signals

Nuclear Activities of Basic Fibroblast Growth Factor: Potentiation of Low-Serum Growth Mediated by Natural or Chimeric Nuclear Localization Signals

Cardiac Alpha₁-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

A unique sequence in the N-terminal regulatory region controls the nuclear localization of KLF8 by cooperating with the C-terminal zinc-fingers

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A GR-motif functions in nuclear accumulation of the large FGF-2 isoforms and interferes with mitogenic signalling

Cited by 32 publications

References 30 publications

Nuclear Activities of Basic Fibroblast Growth Factor: Potentiation of Low-Serum Growth Mediated by Natural or Chimeric Nuclear Localization Signals

Nuclear Activities of Basic Fibroblast Growth Factor: Potentiation of Low-Serum Growth Mediated by Natural or Chimeric Nuclear Localization Signals

Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

A unique sequence in the N-terminal regulatory region controls the nuclear localization of KLF8 by cooperating with the C-terminal zinc-fingers

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Cardiac Alpha₁-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance