Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in approximately half of sporadic (non-familial) VMs, with the cause of the remaining cases unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully
The hyperthermophilic archaeon Methanococcus jannaschii encodes two putative transcription regulators, Ptr1 and Ptr2, that are members of the Lrp/AsnC family of bacterial transcription regulators. In contrast, this archaeon's RNA polymerase and core transcription factors are of eukaryotic type. Using the M. jannaschii high-temperature in vitro transcription system, we show that Ptr2 is a potent transcriptional activator, and that it conveys its stimulatory effects on its cognate eukaryal-type transcription machinery from an upstream activating region composed of two Ptr2-binding sites. Transcriptional activation is generated, at least in part, by Ptr2-mediated recruitment of the TATA-binding protein to the promoter.T he core components of archaeal transcription closely resemble those of eukaryotic RNA polymerase II (1). Archaeal promoters consist of an AϩT-rich TATA-like element recognized by archaeal TATA-binding protein (TBP); the TFIIBrelated transcription factor B (TFB) binds to the TBP-DNA complex and directs a eukaryotic-type RNA polymerase (RNAP) to specifically initiate transcription at an initiator sequence located some 25 bp downstream of the TATA element. Efficient preinitiation complex (PIC) assembly is ensured by the adjacent purine-rich BRE element, which mediates sequencespecific interactions with TFB upstream of the TATA box (2) and dictates the directionality of transcription complex assembly and initiation (3). TBP, TFB, and RNAP are necessary and sufficient to direct transcription at many archaeal promoters in vitro; a modest stimulatory effect of TFE, the archaeal homologue of the ␣ subunit of the RNA polymerase II transcription factor TFIIE, is discerned under conditions of suboptimal TBP-TATA box interaction (4, 5).On the other hand, all archaeal genomes sequenced to date encode potential transcription regulators of bacterial type, underscoring the chimeric nature of the archaeal transcription apparatus (6, 7). Particular interest is attached to the question of how these bacterial-type effectors, especially activators, generate regulation of a eukaryote-like transcription system. All of the putative regulators of transcription that have been characterized in vitro, the metal-dependent repressor 1 (MDR1) from Archaeoglobus fulgidus (8), as well as the homologues LrpA from Pyrococcus furiosus (9, 10), Lrs-14 from Sulfolobus solfataricus (11), and Ptr1 from Methanococcus jannaschii (unpublished results), have only been shown to repress transcription by their cognate RNA polymerases.Here we show that Ptr2, a site-specific helix-turn-helix DNAbinding protein from the hyperthermophilic archaeon M. jannaschii and homologue of the bacterial leucine-responsive regulatory protein (Lrp) family of transcription factors, is a potent transcriptional activator in vitro. We also show that Ptr2 conveys its stimulatory effects on its cognate transcription machinery through direct recruitment of TBP. Materials and MethodsProtein Purification. The RNA polymerase from Methanococcus͞ Methanocaldococcus jannaschi...
Overexpression of MYC oncogene is highly prevalent in many malignancies such as aggressive triple-negative breast cancers (TNBCs) and it is associated with very poor outcome. Despite decades of research, attempts to effectively inhibit MYC, particularly with small molecules, still remain challenging due to the featureless nature of its protein structure. Herein, we describe the engineering of the dominant-negative MYC peptide (OmoMYC) linked to a functional penetrating 'Phylomer' peptide (FPPa) as a therapeutic strategy to inhibit MYC in TNBC. We found FPPa-OmoMYC to be a potent inducer of apoptosis (with IC from 1-2 µM) in TNBC cells with negligible effects in non-tumorigenic cells. Transcriptome analysis of FPPa-OmoMYC-treated cells indicated that the fusion protein inhibited MYC-dependent networks, inducing dynamic changes in transcriptional, metabolic, and apoptotic processes. We demonstrated the efficacy of FPPa-OmoMYC in inhibiting breast cancer growth when injected orthotopically in TNBC allografts. Lastly, we identified strong pharmacological synergisms between FPPa-OmoMYC and chemotherapeutic agents. This study highlights a novel therapeutic approach to target highly aggressive and chemoresistant MYC-activated cancers.
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