Disease relevance of HLH106

• Results of an earlier study showed that efficient activation of transcription from the LDL receptor promoter required domain C of Sp1; however, this domain is not crucial for activation of the simian virus 40 promoter, where synergistic activation occurs through multiple Sp1 binding sites and does not require SREBP [1].

High impact information on HLH106

• Transport is blocked by cholesterol, which triggers SCAP, the SREBP escort protein, to bind to Insigs, which are ER retention proteins [2].
• Importantly, sterol regulation of all promoters studied thus far is mediated by SREBP binding only to SREs [3].
• This nuclear form, which may correspond to proteolytically activated HLH106, is abundant in the blood cell line mbn-2 [4].
• In contrast to the rat homolog, HLH106 transcripts are not more abundant in adipose tissue than in other tissues [4].
• HLH106, a Drosophila transcription factor with similarity to the vertebrate sterol responsive element binding protein [4].

Biological context of HLH106

• HLH106 binds to both palindromic E-boxes and direct repeat sterol regulatory elements (SREs) efficiently, suggesting that it has a dual DNA binding specificity similar to the mammalian proteins [5].
• These findings suggest that the ancestral SREBP pathway functions to maintain membrane integrity rather than to control cholesterol homeostasis [6].
• SREBP-dependent transcriptional activation from all promoters examined thus far is dependent on the presence of an additional binding site for a ubiquitous coactivator [1].

Anatomical context of HLH106

• HLH106 is expressed throughout development, and it is present at high levels in Drosophila cell lines [4].
• We show that phosphatidylethanolamine, the major phospholipid in Drosophila, controls the release of sterol regulatory element-binding protein (SREBP) from Drosophila cell membranes, exerting feedback control on the synthesis of fatty acids and phospholipids [7].
• Rescue by dSREBP requires expression only in fat body and gut [8].

Associations of HLH106 with chemical compounds

• Instead, dSREBP processing is blocked by palmitic acid [6].
• The SREBP pathway in Drosophila: regulation by palmitate, not sterols [6].
• In Drosophila cells, the endogenous SCAP/SREBP complex is transported to Golgi, but transport is blocked by phosphatidylethanolamine instead of sterols [9].

Other interactions of HLH106

• Consistent with this model, a synthetic construct containing three tandem copies of the native LDL receptor SREBP site linked to a single Sp1 site was also significantly activated in a buttonhead-independent fashion [1].

Analytical, diagnostic and therapeutic context of HLH106

• We describe experiments that evaluate the functional equivalence of mammalian SREBPs and the insect homologue of SREBP-1a, HLH106, in both mammalian and insect cell culture systems [5].

References