Transcription Factor

Purpose Pancreatic cancer (PC) is one of the deadliest of all tumors. Previously, we were the first to show that Thymoqui-none (TQ) derived from black seed (Nigella sativa) oil has anti-tumor activity against PC. However, the concentration of TQ required was ...

Abstract Abstract. The highly conserved basic helix-loop-helix transcription factor Hand plays a crucial role in cardiogenesis, limb formation and other developmental processes of vertebrates. Humans, mice and other higher vertebrates have two related genes, dHand (also known as Hand2, Hed, Thing2) and eHand (also known as Hand1, Hxt, Thing1), whereas fish and Drosophila have only a single hand gene. We cloned Drosophila hand and studied the embryonic expression in detail by using various tissue-specific markers that allowed us to analyze the identity of hand-expressing cells. We found hand to be expressed in the entire heart, including all cardioblasts and pericardial cells, in the progenitors of the circular visceral muscles, the lymph gland and garland cells, and in a few cells in the CNS. The expression of Drosophila hand starts after the inductive activity of the early regulators in these tissues, e.g. Tinman and Bagpipe, suggesting a role of Hand in differentiation rather than in tissue determination. In many aspects the expression pattern of Drosophila hand resembles the patterns of its vertebrates orthologues, for instance in cardiac tissues. We assume that Hand proteins might play a highly conserved role throughout evolution. Electronic Supplementary Material is available if you access this article at http://dx.doi.org/10.1007/s00427-002-0268-6. On that page (frame on the left side), a link takes you directly to the supplementary material.

High mobility group (HMG) proteins are chromatin proteins endowed with ‘architectural’ capabilities. HMGA proteins are moderately sequence-specific, and help build enhanceosomes by interacting with partner proteins and binding stably to the minor groove of DNA; their acetylation/deacetylation signal enhanceosome assembly or disassembly. HMGBs are much more dynamic proteins: they have no sequence specificity, and help transcription factors and other nuclear proteins bind to their cognate sites by bending the DNA molecule. However, HMGBs are rarely retained within the complex. Similarly, HMGBs interact with nucleosomes and promote their sliding, but remain bound only for fractions of a second. We argue that HMGBs fluidize chromatin — an action that appears opposite to that of histone H1.

Urogenital birth defects are one of the common phenotypes observed in hereditary human disorders. In particular, limb malformations are often associated with urogenital developmental abnormalities, as the case for Hand-foot-genital syndrome displaying similar hypoplasia/agenesis of limbs and external genitalia. Split-hand/split-foot malformation (SHFM) is a syndromic limb disorder affecting the central rays of the autopod with median clefts of the hands and feet, missing central fingers and often fusion of the remaining ones. SHFM type 1 (SHFM1) is linked to genomic deletions or rearrangements, which includes the distal-less-related homeogenes DLX5 and DLX6 as well as DSS1. SHFM type 4 (SHFM4) is associated with mutations in p63, which encodes a p53-related transcription factor. To understand that SHFM is associated with urogenital birth defects, we performed gene expression analysis and gene knockout mouse model analyses. We show here that Dlx5, Dlx6, p63 and Bmp7, one of the p63 downstream candidate genes, are all expressed in the developing urethral plate (UP) and that targeted inactivation of these genes in the mouse results in UP defects leading to abnormal urethra formation. These results suggested that different set of transcription factors and growth factor genes play similar developmental functions during embryonic urethra formation. Human SHFM syndromes display multiple phenotypes with variations in addition to split hand foot limb phenotype. These results suggest that different genes associated with human SHFM could also be involved in the aetiogenesis of hypospadias pointing toward a common molecular origin of these congenital malformations.

An orthologue of the COE family of helix-loop-helix transcription factors was recovered from the anthozoan Nematostella vectensis (Cnidaria). NvCOE has high sequence similarity to vertebrate and invertebrate orthologues in all three major functional domains of the protein. In situ hybridization studies show early expression through the cleavage period but transcripts are down regulated at gastrulation while remaining expressed at high levels only in the apical tuft of cilia at the aboral end of the planula larva. It is likely that one of the ancestral roles of the COE family of genes may have been in the development of chemosensory neurons.

IL-4 and IL-13 are related cytokines which induce both pro- and anti-inflammatory effects depending on the cell type they act upon and the nature of the receptors expressed. The type I receptor complex is composed of the IL-4Ralpha and gammac and only binds IL-4, whereas, in the type II receptor, IL-4Ralpha dimerizes with IL-13Ralpha1 upon either IL-4 or IL-13 binding. Another ligand binding chain potentially implicated in the IL-4/IL-13 receptor has been described, the IL-13Ralpha2, but the regulation of its expression and its role in IL-4/IL-13 transduction is poorly understood. In this study we report that IL-4 and IL-13 upregulate IL-13Ralpha2 at both the mRNA and protein levels in the keratinocyte cell line HaCaT. In these cells, IL-4 or IL-13 were shown to activate the Janus Kinases JAK1 and JAK2, the transcription factor STAT6, and the ERK and p38 mitogen-activated protein kinases. We show that IL-4 or IL-13-induced IL-13Ralpha2 mRNA expression was inhibited by the ERK inhibitor U0126, the JAK inhibitor AG490 and, to a lesser extent, the p38 MAPK inhibitor SB203580. Moreover, expression of a constitutive active mutant of STAT6 alone did not modify IL-13Ralpha2 mRNA expression, but potentiated the effects of IL-4 or IL-13 on IL-13Ralpha2 expression. The constitutive active mutants of MEK1 or MKK6 increased the level of expression of IL-13Ralpha2 mRNA even in absence of stimulation. Our findings demonstrate, for the first time, that IL-4 and IL-13 can induce IL-13Ralpha2 expression in keratinocytes, and that the ERK and p38 MAPK together with JAK2 and STAT6 play a critical role in this process.