Essay Example on Transcriptional regulation of Arf Transcriptional Control








Transcriptional regulation of Arf Transcriptional control is the most important mechanism of Arf regulation since it has a relatively long half life of 6 hrs 23 Arf reviewed in refs 1 3 10 13 24 A number of transcription factors regulate Arf either positively or negatively Fig 1 The E2F1 transcription factor induces Arf transcription by directly binding to its consensus sequences 25 26 and also the Sp1 sites 27 which are located in the upstream of the exon 1 β thus activating cell growth arrest or apoptosis to avoid the emergence of incipient cancer cells 1 2 E2F2 and E2F3a also transactivates the Arf promoter 26 however this process is modulated differently by the various E2F isoforms For instance E2F3b a splice isoform of E2F3a that is not regulated by E2Fs represses Arf transcription and stimulates cellular growth 28 29 The observation that the loss of Arf can rescue E2F3b depletion mediated cell cycle arrest suggests anti reciprocal correlation between these two proteins 29 To prevent hyperproliferation of cells with oncogenic stress c Myc activates fail safe programs such as apoptosis and cellular senescence by inducing Arf transcription 30 Thus Myc induced Arf activates the p53 signaling preventing immortalization of the murine embryonic fibroblasts MEFs Bouchard et al reported that c Myc signaling increases nuclear FoxO which in turn binds to the Arf promoter to suppresses c Myc driven lymphomagenesis 31 Qi et al showed that Arf inhibits c Myc through physical interaction that is independent of p53 32 When c Myc increases Arf binds to c Myc to block c its ability to activate transcription induce hyperproliferation and transformation In contrast c Myc s ability to repress transcription is unaffected by Arf and c Myc mediated cell death is rather enhanced 32

This direct feedback mechanism represents a p53 independent checkpoint to prevent c Myc mediated tumorigenesis The differential effects of Arf on c Myc function indicate that independent molecular mechanisms mediate c Myc induced hyperproliferation and apoptosis The same group later showed that Egr1 mediates p53 independent c Myc induced apoptosis via an Arf dependent transcriptional mechanism 33 Therefore c Myc Arf binding switches the inherent activity of c Myc from a proliferative to apoptotic protein without p53 through a unique non canonical transcriptional mechanism A cyclin D binding Myb like protein Dmp1 also named Dmtf1 also transactivates the Arf promoter 25 Inoue et al demonstrated that Dmp1 binds to the Ets consensus CCCGGATGC of the mouse Arf promoter and activates its transcription in murine embryonic fibroblasts MEFs which results in Arf p53 dependent cell cycle arrest 25 34 49 Dmp1 reviewed in 50 53 DMP1 α regulates the human ARF promoter the activity of which is antagonized its splice variant DMP1 β 48 49 E2F1 collaborates the Dmp1 to transactivate the Arf promoter to remove early stage neoplastic cells 25 Similar mechanisms must be present in human ARF promoter 27 since both E2F and DMP1 consensus sequences are found in the human version

Arf is actively involved in TGF β signaling Zheng et al reported that TGF β increases the Arf mRNA levels through Smad2 3 and p38MAPKs in MEFs 54 Smad2 3 binds to the Arf promoter on stimulation by TGF β Chromatin immunoprecipitation revealed that TGF β rapidly induces Smad2 3 binding and histone H3 acetylation at the genomic DNA proximal to exon 1 β of Arf followed by increased RNA polymerase II binding increased Arf transcripts and tumor suppression 54 Then the same group showed that TGF β mediated induction of Arf correlated with decreased DNA binding of C EBP β to the Arf promoter 55 In short their results indicate that C EBP β and SP1 are negative and positive Arf regulators that are affected by TGF β Both human and mouse ARF promoters have multiple binding sites for acute myeloid leukemia 1 AML1 which activates its transcription causing cellular senescence in MEFs Interestingly the t 8 21 fusion protein AML1 ETO which is frequently expressed in acute leukemia with low ARF expression 56 Consistently Shikami et al showed that the mRNA expression of p14ARF in t 8 21 AML cells was found to be lower than those without t 8 21 translocation 57 Since p14ARF has been shown to inhibit p53 degradation by binding to MDM2 1 2 repression of p14ARF expression in t 8 21 AML may accelerate the degradation of p53 by MDM2 explaining why genotoxic damage caused by ionizing radiation does not induce p53 response in t 8 21 AML cells Repressors of Arf transcription have been reported and reviewed 50 Fig 2

The polycomb group gene Bmi1 suppresses cellular senescence through repression of Arf transcription 58 Bmi1 deficient MEFs shows decreased cell cycle progression and increased premature senescence which are rescued by Arf Ink4a depletion 59 Bmi1 also requires the EZH2 containing Polycomb Repressive Complex 2 PRC2 to repress ARF INK4a transcription PRC2 maintains the levels of H3K27Me3 as well as the Bmi1 PRC1 complex at the locus The polycomb group gene CBX7 increases the lifespan of normal human cells and MEFs through suppression of Arf Ink4a expression independent of Bmi1 60 TBX2 immortalizes MEFs and decreases senescence in normal human cells by repression of Arf transcription 61 Fig 2 The basic helix loop helix transcription factor Twist1 activates the recruitment of EZH2 to the Arf transcription start site Thus it increases the levels of H3K27Me3 on the ARF INK4a locus followed by repression of Arf transcription 62 63 In general the relative importance of the Arf gene far exceeds that of p16Ink4a in repression of the Arf Ink4a locus in mice reflecting the strong tumor prone tendency of Arf deficient mice 7 64 than p16Ink4a deficient mice 8 9 leaving an open question in human cases since in vivo assays are not possible in the latter

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