| 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 PubMed
Herein, 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
- ↑ Tremblay CS, Huang FF, Habi O, Huard CC, Godin C, Levesque G, Carreau M. HES1 is a novel interactor of the Fanconi anemia core complex. Blood. 2008 Sep 1;112(5):2062-70. doi: 10.1182/blood-2008-04-152710. Epub 2008, Jun 11. PMID:18550849 doi:http://dx.doi.org/10.1182/blood-2008-04-152710
- ↑ 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. 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. Am J Pathol. 2022 May 28. pii: S0002-9440(22)00148-1. doi:, 10.1016/j.ajpath.2022.05.005. PMID:35640677 doi:http://dx.doi.org/10.1016/j.ajpath.2022.05.005
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