A critical role of Sp1 transcription factor in regulating gene expression in response to insulin and other hormones

Solomon, Solomon S.; Majumdar, Gipsy; Martínez-Hernández, Antonio; Raghow, Rajendra

doi:10.1016/j.lfs.2008.06.024

Cited by 111 publications

(87 citation statements)

References 97 publications

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“…A review of Sp1 and Ets1 literature suggests that these factors act as versatile sensors of intrahost cell physiology and signaling (49)(50)(51), which can be exploited by BKPyV for steering its viral life cycle. Ets1 was originally identified as the cellular proto-oncogene counterpart to the retroviral oncogene v-ets (E26 transforming sequence), which acts together with v-Myb protein in an avian erythroblastosis retrovirus, E26.…”

Section: Discussionmentioning

confidence: 99%

Sp1 Sites in the Noncoding Control Region of BK Polyomavirus Are Key Regulators of Bidirectional Viral Early and Late Gene Expression

Bethge

Hachemi

Manzetti

et al. 2015

J Virol

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In kidney transplant patients with BK polyomavirus (BKPyV) nephropathy, viral variants arise bearing rearranged noncoding control regions (rr-NCCRs) that increase viral early gene expression, replicative fitness, and cytopathology. rr-NCCRs result from various deletions and duplications of archetype NCCR (ww-NCCR) sequences, which alter transcription factor binding sites (TFBS). However, the role of specific TFBS is unclear. We inactivated 28 TFBS in the archetype NCCR by selective point mutations and examined viral gene expression in bidirectional reporter constructs. Compared to the archetype, group 1 mutations increased viral early gene expression similar to rr-NCCR and resulted from inactivating one Sp1 or one Ets1 TFBS near the late transcription start site (TSS). Group 2 mutations conferred intermediate early gene activation and affected NF1, YY1, and p53 sites between early and late TSS. BK polyomavirus (BKPyV) is one of now more than 12 human PyVs (1) and is known to infect more than 90% of the human population during early childhood (2-6). Following primary infection, BKPyV persists latently in the renourinary tract, with intermittent periods of asymptomatic shedding into urine (5, 7). BKPyV disease typically occurs in individuals with altered immune functions, to which viral determinants are thought to contribute (3, 8). Thus, BKPyV causes nephropathy in 1 to 14% of kidney transplant patients and hemorrhagic cystitis in 5 to 20% of allogeneic hematopoietic stem cell transplant recipients (2, 9).BKPyV strains excreted in urine of healthy immunocompetent individuals typically bear a noncoding control region (NCCR) of linear archetype (ww) architecture (ww-NCCR) (5, 10, 11) and grow slowly in primary human urothelial and renal tubular epithelial cells (8,12). In immunosuppressed kidney transplant patients with early stages of BKPyV-associated nephropathy, the virus contains mostly archetype ww-NCCR (8, 13). However, when immunosuppression is not readily reduced to permit specific T cells to resume control over BKPyV replication (14-17), viral variants with rearranged NCCRs (rr-NCCRs) emerge that are associated with higher plasma viral loads and more severe renal allograft pathology (8). Similar rr-NCCRs of JC polyomavirus have been linked with the emergence of progressive multifocal leukoencephalopathy, a debilitating, often fatal brain disease in immunocompromised patients with HIV/AIDS or receiving transplantation or therapies for cancer and immune diseases (18)(19)(20)(21)(22). The archetype NCCR of polyomaviruses is approximately 400 bp in length and harbors the origin of replication as well as bidirectional promoter/ enhancer functions that, in concert with the host cell signals, control the timing and sequential activation of early viral gene region (EVGR) expression, viral DNA genome replication, and late viral gene region (LVGR) expression. Notably, EVGR and LVGR are encoded and transcribed in opposite directions from the NCCR (23). The ϳ2.3-kb EVGR encodes the small T antigen, the large ...

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Section: Discussionmentioning

confidence: 99%

Sp1 Sites in the Noncoding Control Region of BK Polyomavirus Are Key Regulators of Bidirectional Viral Early and Late Gene Expression

Bethge

Hachemi

Manzetti

et al. 2015

J Virol

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“…SP1 can activate and repress many genes in response to physiological and pathological stimuli (32,33). The protein is known to be O-GlcNAcylated, and this modification regulates its effects on the expression of other genes, especially those important in insulin signaling and metabolic syndrome (32).…”

Section: Discussionmentioning

confidence: 99%

“…The protein is known to be O-GlcNAcylated, and this modification regulates its effects on the expression of other genes, especially those important in insulin signaling and metabolic syndrome (32). Insulininduced O-GlcNAcylation of SP1 causes its transition to the nucleus (34), and its glucosamine-induced glycosylation is known to protect SP1 from proteasomal degradation (35).…”

Section: Discussionmentioning

confidence: 99%

Cellular Content of UDP-N-acetylhexosamines Controls Hyaluronan Synthase 2 Expression and Correlates with O-Linked N-Acetylglucosamine Modification of Transcription Factors YY1 and SP1

Jokela

Makkonen

Oikari

et al. 2011

Journal of Biological Chemistry

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Hyaluronan, a high molecular mass polysaccharide on the vertebrate cell surface and extracellular matrix, is produced at the plasma membrane by hyaluronan synthases using UDP-GlcNAc and UDP-GlcUA as substrates. The availability of these UDP-sugar substrates can limit the synthesis rate of hyaluronan. In this study, we show that the cellular level of UDP-HexNAc also controls hyaluronan synthesis by modulating the expression of HAS2 (hyaluronan synthase 2). Hyaluronan, a non-sulfated glycosaminoglycan present on the vertebrate cell surface and extracellular matrix, is involved in cellular functions, including migration, proliferation, adhesion, and various signaling systems, by its unique physicochemical properties and interactions with specific cell surface receptors (1). Hyaluronan is synthesized by HAS1-3, integral plasma membrane proteins that use cytosolic UDP-GlcNAc and UDPGlcUA as substrates to produce the long linear hyaluronan chains. During its synthesis, the growing hyaluronan chain runs through a pore in the plasma membrane into the extracellular matrix (2).Changes in hyaluronan production have been associated mostly with the expression level of HAS genes (3-6), especially in keratinocytes (7-13). Of the three genes, particularly HAS2 is subject to regulation by growth factors, cytokines, and hormones (4,14,15). In keratinocyte cultures, EGF, keratinocyte growth factor, TNF␣, and retinoic acid induce, whereas TGF␤ inhibits, HAS2 expression (8, 10, 13, 16). Accordingly, the HAS2 promoter has been shown to contain functional response elements (REs) 3 for different transcription factors, including retinoid acid receptor, NF-B, CREB1 (cAMP response elementbinding protein 1), and SP1 (specificity protein 1) (7,11,16).Besides by the protein expression of hyaluronan synthase (HAS) enzymes, hyaluronan synthesis is also controlled by the availability of the hyaluronan precursors, the substrates of HAS. Raising cellular UDP-GlcUA content stimulates hyaluronan synthesis, whereas a low concentration of UDP-GlcUA can limit the synthesis (12, 17). We have shown that the same applies to UDP-GlcNAc: limiting or increasing its content stimulates and inhibits, respectively, the synthesis of hyaluronan (18).The cellular content of UDP-GlcNAc makes an interesting connection between hyaluronan synthesis and cellular energy metabolism. UDP-GlcNAc is a product of the hexosamine synthesis pathway, into which 2-5% of the cellular influx of glucose is shunted (19). The rate-limiting step in hexosamine synthesis from glucose to UDP-GlcNAc is considered to be the GFAT1 (glutamine:fructose-6-phosphate amidotransferase 1) and GFAT2 isoenzymes (20). The flux of glucose through the hexosamine pathway serves as a cellular sensor of glucose availability, and it regulates the expression of a number of genes 3 The abbreviations used are: RE, response element; HAS, hyaluronan synthase; CBP, cAMP response element-binding protein-binding protein; PCAF, p300/CBP-associated factor.

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“…DNA binding of Sp1 is mediated through three zinc fingers in the C-terminal region, which recognize GC-rich elements in a large number of promoters that are frequently found in euchromatic CpG islands. Posttranslational modifications throughout Sp1, including phosphorylation, acetylation, O-linked glycosylation, and sumoylation, modulate its interaction with chromatin remodeling factors, DNA, transcription machinery, and other transcription factors to enhance or repress gene expression (13,35,36,40,51,53,56,69,82). Our group and others have shown that transcription factor Sp1, which contains two S/TQ cluster domains (SCDs), characteristic of phosphoinositide 3-kinase-like kinase (PI3KK) substrates, is phosphorylated by the ataxia telangiectasia mutated kinase (ATM) in response to ionizing radiation, H 2 O 2 (64), and other DNA-damaging agents (unpublished data), as well as herpesvirus infection (33).…”

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confidence: 99%

Sp1 Facilitates DNA Double-Strand Break Repair through a Nontranscriptional Mechanism

Beishline

Kelly

Olofsson

et al. 2012

Molecular and Cellular Biology

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cSp1 is a ubiquitously expressed transcription factor that is phosphorylated by ataxia telangiectasia mutated kinase (ATM) in response to ionizing radiation and H 2 O 2 . Here, we show by indirect immunofluorescence that Sp1 phosphorylated on serine 101 (pSp1) localizes to ionizing radiation-induced foci with phosphorylated histone variant ␥H2Ax and members of the MRN (Mre11, Rad50, and Nbs1) complex. More precise analysis of occupancy of DNA double-strand breaks (DSBs) by chromatin immunoprecipitation (ChIP) shows that Sp1, like Nbs1, resides within 200 bp of DSBs. Using laser microirradiation of cells, we demonstrate that pSp1 is present at DNA DSBs by 7.5 min after induction of damage and remains at the break site for at least 8 h. Depletion of Sp1 inhibits repair of site-specific DNA breaks, and the N-terminal 182-amino-acid peptide, which contains targets of ATM kinase but lacks the zinc finger DNA binding domain, is phosphorylated, localizes to DSBs, and rescues the repair defect resulting from Sp1 depletion. Together, these data demonstrate that Sp1 is rapidly recruited to the region immediately adjacent to sites of DNA DSBs and is required for DSB repair, through a mechanism independent of its sequence-directed transcriptional effects.T ranscription factor Sp1 regulates the expression of genes involved in cell proliferation, DNA repair, and apoptosis/ senescence (9). DNA binding of Sp1 is mediated through three zinc fingers in the C-terminal region, which recognize GC-rich elements in a large number of promoters that are frequently found in euchromatic CpG islands. Posttranslational modifications throughout Sp1, including phosphorylation, acetylation, O-linked glycosylation, and sumoylation, modulate its interaction with chromatin remodeling factors, DNA, transcription machinery, and other transcription factors to enhance or repress gene expression (13,35,36,40,51,53,56,69,82). Our group and others have shown that transcription factor Sp1, which contains two S/TQ cluster domains (SCDs), characteristic of phosphoinositide 3-kinase-like kinase (PI3KK) substrates, is phosphorylated by the ataxia telangiectasia mutated kinase (ATM) in response to ionizing radiation, H 2 O 2 (64), and other DNA-damaging agents (unpublished data), as well as herpesvirus infection (33).Genomic stability is maintained by the cellular response to DNA damage. In response to DNA double-strand breaks (DSBs), ATM is activated (80) and initiates a cascade of DNA damage signals by phosphorylation of hundreds of proteins involved in cell cycle checkpoint activation, DNA repair, and apoptosis, including p53, Chk2, ␥H2Ax, BRCA1, and Nbs1 (48, 57). Mutations in the ATM gene result in the autosomal recessive disorder ataxia telangiectasia (AT), which is characterized by radiation sensitivity, immunodeficiency, neurodegeneration, and cancer predisposition (79). Cells derived from AT patients exhibit increased chromosome breaks, defects in cell cycle checkpoints, and increased sensitivity to ionizing radiation (IR) (66,78). Inactive ATM forms...

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A critical role of Sp1 transcription factor in regulating gene expression in response to insulin and other hormones

Cited by 111 publications

References 97 publications

Sp1 Sites in the Noncoding Control Region of BK Polyomavirus Are Key Regulators of Bidirectional Viral Early and Late Gene Expression

Sp1 Sites in the Noncoding Control Region of BK Polyomavirus Are Key Regulators of Bidirectional Viral Early and Late Gene Expression

Cellular Content of UDP-N-acetylhexosamines Controls Hyaluronan Synthase 2 Expression and Correlates with O-Linked N-Acetylglucosamine Modification of Transcription Factors YY1 and SP1

Sp1 Facilitates DNA Double-Strand Break Repair through a Nontranscriptional Mechanism

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