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Post-Translational Control of Sp-Family Transcription Factors

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Post-Translational Control of Sp-Family Transcription Factors Current Genomics, 2008, 9, 301-311 301 Post-Translational Control of Sp-Family Transcription Factors J.S. Waby, C.D. Bingle and B.M. Corfe* School of Medicine and Biomedical Sciences, University of Sheffield, Royal Hallamshire Hospital, Sheffield, S10 2JF, UK Abstract: Sp-family transcription factors are widely expressed in human tissues and involved in the regulation of many cellular processes and response to cellular microenvironment. These responses appear to be mediated by alterations in transcription factor affinity for DNA rather than altered protein level. How might such changes be effected? This review will identify the range of known post-translational modifications (PTMs) of Sp-factors and the sometimes conflicting lit- erature about the roles of PTMs in regulating activity. We will speculate on the interaction between cell environment, chromatin microenvironment and the role of PTM in governing functionality of the proteins and the complexes to which they belong. Received on: April 11, 2008 - Revised on: May 14, 2008 - Accepted on: May 15, 2008 Key Words: Sp family, Sp1, Sp3 phosphorylation, acetylation, glycosylation, sumolation. INTRODUCTION Both Sp1 and Sp3 have been shown to exhibit ubiquitous expression, whereas Sp4 expression is restricted to brain and The Sp/KLF family is divided into two major subgroups: developing testis. Sp2 expression has been observed in a the Sp-family, which are highly homologous to Sp1 in the number of cell lines, however, no data is available regarding zinc finger region; and the KLF family which are more het- tissue expression levels [7]. Sp7 was identified as a bone erogenous and are named after the Drosophila segmentation specific transcription factor required for osteoblast differen- gene Kruppel which also contains 3 zinc finger motifs [1]. tiation and bone formation [8]. The expression patterns of The Sp-family is made up of 8 genes Sp1-8, each located Sp5, Sp6 and Sp8 have yet to be investigated. The first four adjacent to a HOX gene cluster and the KLF family contains members of the Sp-family, Sp1-4, are more closely related to 15 known members [2]. Specificity protein/Kruppel-like each other than to Sp5-8. Sp1-4 contain an N-terminal acti- factor (Sp/KLF) family of transcriptions factors are charac- vation domain and a C-terminal DNA binding domain. Sp3 terised by the presence of 3 highly conserved zinc finger also contains an inhibitory domain which is thought to medi- domains which confer DNA-binding ability. Due to this con- ate suppression of Sp3 transcription activation. Sp3 is inac- served DNA-binding motif, members of the Sp/KLF family tive or only weakly active and is thought to act as a repressor share the same DNA recognition sites, namely GC for Sp1 activated genes by competing for the same binding (GGGGCGGGG) and GT (GGTGTGGGGG) boxes. The sites [9]. Sp5-8 proteins are shorter, lacking the N-terminal affinity of Sp/KLF proteins for these sites varies due to small activation domain of Sp1-4 which may explain their de- amino acid sequence changes in the recognition domain. creased transcription activation potential. The regulation of transcription by ubiquitously expressed Little is known regarding the function of Sp5-8. The transcription factors of this family is not generally thought to creation of knock out mice has provided some insight into occur through protein turnover, thereby invoking a key role the possible regulatory roles of Sp1-4. Sp1 null mice show for post-translational modification of Sp proteins in govern- severely retarded embryonic development and die after em- ing transcriptional activity. bryonic day 10 (E10) [10]. This evidence indicates that Sp1 is essential for normal embryonic development. Targeted The SP-Family homologous recombination of the Sp3 gene produced Sp-/- Sp1, the first identified member of this family [3, 4] was embryos which exhibited late and impaired tooth and bone shown to be a transactivator of the simian virus 40 (SV40) development. Sp3-/- mice survived gestation, but died of res- early promoter [5, 6]. Since then seven further members of piratory failure perinatally [11]. These observations suggest this family have been identified and were numbered Sp2-8, that both Sp1 and Sp3 are involved in developmental regula- according to their order of discovery. The functional roles of tion of gene expression. Both Sp1 and Sp3 show increased the members of the Sp family have been investigated to vari- expression in a number of cancers suggesting that these tran- able degrees with the most data having been collected for scription factors are switched back on during cancer cell Sp1 and Sp3. differentiation. Virus particles are also known to ‘hijack’ Sp1/3 during viral replication and Sp1 appears to be a spe- cific target of the SV40 virus. The function of Sp2 is poorly *Address correspondence to this author at the School of Medicine and Bio- understood, however, it is clearly separate from the function medical Sciences, University of Sheffield, Royal Hallamshire Hospital, of other Sp proteins as Sp2 preferentially binds GT boxes not Sheffield, S10 2JF, UK; E-mail: [email protected] 1389-2029/08 $55.00+.00 ©2008 Bentham Science Publishers Ltd. 302 Current Genomics, 2008, Vol. 9, No. 5 Waby et al. GC boxes [7]. Sp2 overexpression has been noted in late sponse to HSV-1 viral infection. This hyperphosphorylation stage human prostate tumours and may be oncogenic [12]. requires the presence of a member of the phosphatidylinosi- tol 3 -like kinase family, Ataxia telangiectasia mutated pro- Sp4 knock out mice show a complex phenotype, different -/- tein (ATM) [16]. There are multiple explanations for the to that observed in Sp1 and Sp3 null mice. Sp4 mice de- velop normally until birth, however, within four weeks two enhanced phosphorylation state of Sp1 following viral infec- -/- tion. Firstly it is possible that phosphorylation may result in thirds of pups die. The surviving Sp4 mice exhibit retarded an increased DNA binding affinity, which could mediate growth and males do not breed due to an absence of mount- viral “hijacking” of the transcriptional machinery. This ing behaviour, which has been shown to be linked to brain would fit with the observed increase in activation of a HIV-1 abnormalities [13]. luciferase reporter construct following HIV-1 infection [15]. The Sp-family transcription factors appear to have di- Conversely, enhanced Sp1 phosphorylation and DNA bind- verse roles which require further characterisation. This is ing may be a protective effect to increase the transcription of especially apparent for Sp5-8 proteins which are poorly un- ‘cellular defence’ genes in the infected cell. Thirdly, Sp1 derstood. increased GC-box binding may act to activate the apoptotic pathway and initiate death of infected cells. In support of POST-TRANSLATIONAL MODIFICATIONS this, Sp1 phosphorylation has been shown to activate RasL Transcriptional control may be exerted via shutdown of transcription [17]. However phosphorylation of Sp1 is obvi- Sp transcription factor translation, however such a crude ously more complex than a simple on-off switch model as method of transcriptional control would not be immediately viral infection induced phosphorylation is reported to have effective as proteosomal degradation of proteins is not in- either no effect or an activation effect on transcription [15, stantaneous. A more refined method would be to modify 16]. reversibly Sp-family proteins in a manner which affects their Evidence regarding the role of phosphatases in Sp1 tran- efficacy. PTMs, provide a means of changing the protein scriptional regulation is contradictory, however, the literature structure to affect transcription without having to degrade or concurs that phosphatase proteins 1 and 2(A) are involved. create de novo transcription factor. There is a significant The majority of evidence suggests that dephosphorylation of body of evidence for the post translational modification of Sp1 causes a decrease in DNA binding and reduced tran- Sp-family proteins in the form of phosphorylation, acetyla- scriptional activation, however a number of studies only in- tion, glycosylation and sumolation. This evidence will be fer Sp1 dephosphorylation and do not specify the residues discussed here, however, as Sp1 and Sp3 are the best studied which are dephosphorylated [18-24]. Contradictory to the the majority of post translational modification data comes main body of evidence, PP2A inhibition with okadaic acid from these two family members. The high homology be- was shown to increase Sp1 Phosphorylation and HIV pro- tween Sp proteins, especially Sp1-4, suggests that roles of moter transcription with no observable effect on Sp1 DNA post translational modifications in the transcriptional control binding. PP2A dephosphorylation of Sp1 has also been re- of one Sp member may also be relevant to others Sp pro- ported to increase the association of dephosphorylated Sp1 teins. with the chromatin fraction in a crude chromatin preparation [25]. Furthermore the dephosphorylation of Sp1 has been Phosphorylation shown to increase Sp1 binding affinity to an inducible Phosphorylation appears to play a key role as a molecular AAAT promoter element [18]. ‘on-off’ switch in a plethora of biological processes. There is Although there appear to be exceptions, generally phos- a body of evidence to suggest a role for phosphorylation in phorylation acts to increase DNA binding and transcriptional transcription factor regulation. The initial suggestion that Sp-
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