SIRT7 interacts with RNA polymerase I histones to promote Pol I-m

SIRT7 interacts with RNA polymerase I histones to promote Pol I-mediated rRNA transcription in the nucleolus [12]. SIRT1 is the most studied sirtuin Ponatinib AP24534 family member, mainly due to its purported ability to promote longevity in yeast, worms, drosophila and mammals [13], [14], [15], [16]. However its ability to increase the life span of lower organisms has recently been called into question [17]. SIRT1 has also been suggested to have a critical role in tumorigenesis, however it is controversial whether SIRT1 is a tumor-suppressor or a tumor-promoter and in fact it is likely to be tumor-type specific [18]. SIRT1′s deacetylase activity plays an important function in normal and malignant cellular processes by targeting histones, which results in a tighter chromatin structure and transcriptional repression [19].

Importantly, SIRT1 also modulates the stability and/or activation potential of a broad range of transcription factors, such as p53 [20], [21], FOXO [22], Ku70 [23], NF-��B [24], E2F1 [25] and PPAR�� co-activator 1�� (PGC-1��) [26] and as recently described the hypoxia-inducible transcription factors (HIF), HIF-1 [27] and HIF-2 [28]. HIF transcription factors are the key mediators of oxygen homeostasis under hypoxic conditions and they play a vital role in embryonic development, physiological responses and in disease pathologies. HIF heterodimers are composed of an oxygen-sensitive ��-subunit and a constitutively expressed ��-subunit. HIF-1 and HIF-2 are the best-characterized isoforms and are mainly regulated by posttranslational modifications of their ��-subunit [29].

Specific prolyl hydroxylases (PHD), which depend on the substrates oxygen, Fe (II) and 2-oxoglutarate, target the ��-subunit under normoxic conditions [30]. Hydroxylation of two proline residues (HIF-1��: P402 and P564 and HIF-2��: P405 and P531) within the oxygen-dependent degradation domain serve as a recognition site for the von Hippel-Lindau tumor suppressor (pVHL), a ubiquitin E3 ligase, which leads to the proteosomal degradation of the ��-subunit [31], [32], [33]. In the absence of oxygen, PHDs are inactive and thereby HIF�� proteins are stabilized. Accumulated HIF�� protein translocates to the nucleus, forms a dimer with HIF�� and along with co-activators such as p300-CBP binds to hypoxia responsive elements (HRE) of target genes.

HIF-1 and HIF-2 share the same consensus sequence G/ACGTG in their target genes [34] and have several common gene targets such as erythropoietin (EPO), vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT-1) [35]. However, they also have unique transcriptional targets, HIF-1 is responsible GSK-3 for the regulation of many genes encoding enzymes involved in the glycolytic pathway, as well as the pro-apoptotic gene BCL2 adenovirus E1B-interacting protein 1 (BNIP3) and carbonic anhydrase 9 (CA9) [36], [37].

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