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New Aspects of Isotretinoin Teratogenicity
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
Hox genes play an important part in the patterning of limbs, vertebrae, and craniofacial structures by providing an ordered molecular system of positional values, termed the Hox code. ATRA alters hindbrain Hox code and induces transformation of rhombomeres 2/3 into a 4/5 identity (51). HOX transcription factors, which are induced by ATRA (52–54), play a crucial role in NCC-dependent branchial arch pattering (55–58). ATRA induces Hox gene expression, a regulatory mechanism related to ATRA's teratogenic activity (53). Intriguingly, HOX binding sites have been identified on the TP53 promoter and compromised HOXA5 function limited p53 expression (59). As a result, ATRA-induced HOX gene expression may further enhance p53 expression, explaining the interplay between ATRA, HOX, and p53 in isotretinoin teratogenicity (Figure 10.1). Isotretinoin-stimulated overactivation of p53-mediated apoptosis of NCCs may represent the molecular basis for craniofacial abnormalities associated with isotretinoin embryopathy.
TP53 in cancer origin and treatment
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Elena A. Komarova, Peter M. Chumakov, Andrei V. Gudkov
Transcriptional regulation of the TP53 gene might play an important role since: (i) attenuated transcription of wild type TP53 can be involved in its inactivation in tumors (Raman et al., 2000); (ii) the level of TP53 mRNA determines the susceptibility of normal tissues to apoptosis in response to genotoxic stress (Komarova et al., 1997a, 2000; Zhao et al., 2000); and (iii) mutant TP53 genes are generally expressed at higher levels due in part to increased rates of transcription of the gene (Balint and Reisman, 1996). The relatively well-characterized mouse tp53 promoter contains binding sites and is controlled by a number of regulatory transcription factors. The promotor includes an E-box motif that serves as a recognition site for members of the basic-helix-loop-helix family of transcription factors (Ronen et al., 1991). USF and Myc/Max bind to this site in the promoter (Reisman and Rotter, 1993; Reisman et al., 1993) and positively regulate TP53 transcription. NFkB, NF1, SP1, PF1, PF2, PBF I and II are among the factors regulating transcription activity of TP53 (Reisman and Loging, 1998). It was recently shown that HOXA5 is involved in positive regulation of the human TP53 promoter. Down-regulation of HOXAS in breast carcinomas bearing wild-type TP53 is likely to be the cause of low expression of the TP53 gene in these tumors; ectopic expression of HOXAS in such tumors results in apoptosis that does not occur if TP53 is inactivated (Raman et al., 2000).
Homeobox A5 and A9 expression and beta-thalassemia
Published in British Journal of Biomedical Science, 2021
EAE Badr, IE-T El-Sayed, MKR Alasadi
Data from zebrafish point to Homeobox (Hox) genes having an important role in normal haematopoiesis related to haematopoietic stem cells (HSCs) and early haematopoietic progenitors [6]. The Hox genes contain several clusters (A-D). Each cluster consists of paralog groups with nine to eleven members assigned on the basis of sequence similarity and relative position within the cluster [7]. The HOXA family encodes proteins that contain the DNA-binding homeobox motif and controls the early patterns of embryo segmentation. Although HOX expression is typically inhibited in adults, reactivation may occur with various homoeostatic cellular processes including haematopoiesis. Hox genes are required for the maintenance of progenitor or stem cell status, promoting their proliferation. HoxA9 is the most preferentially expressed Hox gene in human CD34+ HSCs and early haematopoietic progenitors [8]. HoxA5 has two effects on erythropoiesis: it causes a predominance of mature erythroid lineage cells and the partial apoptosis of erythroid progenitors. RNA-seq indicates that multiple biological processes including erythrocyte homoeostasis, cell metabolism, and apoptosis are modified by HoxA5 [9]. We hypothesized roles for HoxA9 and HoxA5 in β-thalassemia.
Role and molecular mechanism of stem cells in colorectal cancer initiation
Published in Journal of Drug Targeting, 2020
Meng-Yan Wang, Yu-Han Qiu, Mei-Lian Cai, Cong-Hui Zhang, Xiao-Wei Wang, Hong Liu, Yi- Chen, Wu-Li Zhao, Jing-Bo Liu, Rong-Guang Shao
HOXA5 is a member of the homologous nuclear (HOX) family and is located on chromosome 7 (7p13.2). It is located in the nucleus of cells of the intestinal villus and has an antagonistic effect on the Wnt pathway such that it inhibits the stem cell phenotype and contributes to differentiation. In colorectal CSCs, the Wnt pathway contributes to c-myc expression, and then, c-myc binds with MIZ (a traditional transcriptional activator), forming a complex. Subsequently, the complex can inhibit HOXA5 transcription to suppress β-catenin expression, thereby inhibiting the expression of the β-catenin target genes associated with the survival of CSCs. Furthermore, the researchers found that high expression of HOXA5 could increase the expression of the differentiation indicators, such as APCDD1, CXXC4 and NKD1 that are the inhibition of the Wnt pathway activation in villus cells [49].
British Journal of Biomedical Science in 2021. What have we learned?
Published in British Journal of Biomedical Science, 2021
Continuing in Issue 3, a study of β-thalassaemia investigated the role of the Homeobox (Hox) genes in this group of disorders as data from zebrafish suggest these have an important role in normal haematopoiesis (Reference). β-thalassaemia is a spectrum of hereditary blood disorders characterized by defects in the synthesis of the β chains of haemoglobin. The severity of symptoms is related to the extent of absent production of β-globin chain (these range from severe to asymptomatic). The genotypic variability of β-globin synthesis is designated as β(+) for decreased production and β(0) for absent production. The phenotypic variability is designated as either minor, intermediate, or major. β-thalassaemia minor is heterozygosity with one unaffected beta-globin gene and one affected, either β(+) or β(0). Homozygosity or compound heterozygosity with β(+) or β(0) causes intermediate and major. The molecular defects in β-thalassaemia result in absent or reduced β-chain production. Alpha chain synthesis is unaffected, and hence there is an imbalanced globin chain production leading to an excess of α chains. In the absence of their partners, they are unstable, and they precipitate in the red cell precursors, giving a rise to large intracellular inclusions, which interfere with red cell maturation. The Hox genes are heavily involved in embryo segmentation with two members HoxA9 and HoxA5 expressed in red cell progenitors. Badr et al [14] showed an increase in HoxA9 in β-thalassaemia patients that was related to disease severity. The authors hypothesise this could be due to increased self-replication of the haematopoetic stem cells. They found no changes in HoxA5 suggesting this gene has no role in this process. The authors acknowledge it as a case control study and that there may be misdiagnoses or bias as well as the effects of transfusion. However, HoxA gene analysis shows promise in the identification of patients with thalassaemia and in differentiating between its two subtypes of major and intermediate thalassaemia.