7c4o | pdb_00007c4o
Solution structure of the Orange domain from human protein HES1
Structural highlights
Function[HES1_HUMAN] Transcriptional repressor of genes that require a bHLH protein for their transcription. May act as a negative regulator of myogenesis by inhibiting the functions of MYOD1 and ASH1. Binds DNA on N-box motifs: 5'-CACNAG-3' with high affinity and on E-box motifs: 5'-CANNTG-3' with low affinity (By similarity). May play a role in a functional FA core complex response to DNA cross-link damage, being required for the stability and nuclear localization of FA core complex proteins, as well as for FANCD2 monoubiquitination in response to DNA damage.[1] Publication Abstract from PubMedHerein, we report that hairy and enhancer of split homolog-1 (HES1), known to repress gene transcription in progenitor cells of several cell lineages, is strongly expressed in cells and tissues of T-cell lymphoma expressing the oncogenic chimeric tyrosine kinase nucleophosmin (NPM)-anaplastic lymphoma kinase [ALK; ALK(+) T-cell lymphoma (TCL)]. The structure analysis of the Orange domain of HES1 indicates that HES1 forms a highly stable homodimer. Of note, repression of HES1 expression leads to inhibition of ALK(+) TCL cell growth in vivo. The expression of the HES1 gene is induced by NPM-ALK through activation of STAT3, which binds to the gene's promoter and induces the gene's transcription. NPM-ALK also directly phosphorylates HES1 protein. In turn, HES1 up-regulates and down-regulates in ALK(+) TCL cell expression of numerous genes, protein products of which are involved in key cell functions, such as cell proliferation and viability. Among the genes inhibited by HES1 is thioredoxin-interacting protein (TXNIP), encoding a protein implicated in promotion of cell death in various types of cells. Accordingly, ALK(+) TCL cells and tissues lack expression of TXNIP, and its transcription is co-inhibited by HES1 and STAT3 in an NPM-ALK-dependent manner. Finally, the induced expression of TXNIP induces massive apoptotic cell death of ALK(+) TCL cells. The results revealed a novel NPM-ALK-controlled pro-oncogenic regulatory network and document an important role of HES and TXNIP in the NPM-ALK-driven oncogenesis, with the former protein displaying oncogenic and the latter tumor suppressor properties. Induction of Transcriptional Inhibitor Hairy and Enhancer of Split Homolog-1 and the Related Repression of Tumor-Suppressor Thioredoxin-Interacting Protein Are Important Components of Cell-Transformation Program Imposed by Oncogenic Kinase Nucleophosmin-Anaplastic Lymphoma Kinase.,Zhang Q, Wang HY, Nayak A, Nunez-Cruz S, Slupianek A, Liu X, Basappa J, Fan JS, Chekol S, Nejati R, Bogusz AM, Turner SD, Swaminathan K, Wasik MA Am J Pathol. 2022 May 28. pii: S0002-9440(22)00148-1. doi:, 10.1016/j.ajpath.2022.05.005. PMID:35640677[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
