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Congenital Central Hypoventilation Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Belonging to the Ensembl protein family, PHOX2B functions as a homeobox domain transcription factor of several genes essential for the development of neural crest derivatives and hindbrain motor neuron, including TH, DBH (dopamine β-hydroxylase), PHOX2A (paired-like homeobox 2A), PHOX2B itself, RET (rearranged during transfection), TLX2 (T-cell leukemia homeobox 2), ALK (anaplastic lymphoma kinase), SOX10, Hand1, SCG2, and MSX1. In addition, through interaction with PHOX2B, CREB-binding protein (CREBBP/CBP) and TRIM11 may co-mediate synergistic trans-activation.
Hypoplastic left heart syndrome (HLHS): molecular pathogenesis and emerging drug targets for cardiac repair and regeneration
Published in Expert Opinion on Therapeutic Targets, 2021
Anthony T Bejjani, Neil Wary, Mingxia Gu
It was previously shown that NKX2-5 and HAND1 are required for the development of the left ventricle [25]. Moreover, NOTCH1, NKX2-5, and HAND1 were shown to synergistically activate the expression of SRE, TNNT2, and NPPA [25]. Mutations in both NKX2-5 and HAND1 have been reported in HLHS patients and patient-derived iPSCs. Chromatin immunoprecipitation (ChIP) analyses revealed an increase in inhibitory H3K27me3 marks on the NKX2-5 promoter, at the expense of a reduction in H3K4me2 marks, which promote transcriptional activation [25]. This suggests that epigenetics could be an underlying cause in HLHS phenotype and should be further examined in future studies.
Thymosin β4 and the vasculature: multiple roles in development, repair and protection against disease
Published in Expert Opinion on Biological Therapy, 2018
The suggestion that Tβ4 may promote mural cell differentiation via the TGFβ pathway is consistent with a mechanism proposed for differentiation of the yolk sac vasculature. Tβ4 was identified by representational difference analysis [47], and confirmed by chromatin immunoprecipitation and transcriptional assays [4], to be a downstream target of the basic helix-loop-helix transcription factor, Hand1. Hand1-null embryoid bodies revealed vascular differentiation defects and Hand1-null embryos displayed defective yolk sac vasculogenesis [4]. Exogenous administration of TB4 rescued expression of EC and SMC markers in Hand1-null embryoid body cultures and, moreover, rescued Hand1-null embryos to prolong survival. In contrast to control embryos, which developed within a yolk sac with an organized capillary plexus, null embryos lacked yolk sac vascular plexus formation and arrested in development by embryonic day (E)8.5. Injection of pregnant female mice with TB4 was sufficient to rescue Hand1-null embryos, which were recovered at E8.5 with an appropriately formed yolk sac capillary network and in which the embryos had developed beyond the arrested stage of the mutants. Mechanistically, genes of the TGFβ and Notch signaling pathways, which were found to be dysregulated in Hand1 mutant yolk sacs, were rescued to control levels with TB4 treatment [4]. It is not known whether Hand1 also regulates Tβ4 expression at later embryonic stages, perhaps at the time points when Tβ4 is required for systemic or coronary vasculogenesis, nor is it fully understood how Tβ4 impacts on the key vasculogenic signaling pathways, those that regulate EC proliferation, migration, and differentiation, that include, but may not be limited to, TGFβ and Notch1.
PLK4: a link between centriole biogenesis and cancer
Published in Expert Opinion on Therapeutic Targets, 2018
Radhika Radha Maniswami, Seema Prashanth, Archana Venkataramana Karanth, Sindhu Koushik, Hemalatha Govindaraj, Ramesh Mullangi, Sriram Rajagopal, Sooriya Kumar Jegatheesan
PLK4 is necessary for the nucleolar export of HAND1, an important transcription factor involved in the differentiation of trophoblast stem cells into trophoblast giant cells during placental development [100–102]. PLK4 phosphorylation on two critical residues of HAND1 prevents HICp40 binding-induced inactivation of HAND1 in the nucleolus. This results in the release of HAND1 from the nucleolus and promotes transcription of HAND1 target genes, thus initiating the differentiation of trophoblast stem cells [100].