Human Bex2 interacts with LMO2 and regulates the transcriptional activity of a novel DNA-binding complex

Han, Chao; Líu, Hao; Liu, Jin; Yin, Kang; Xie, Yi; Wang, Yong; Yuan, Jiangang; Qiang, Bo; Liu, Yongjian; Peng, Xiaozhong

doi:10.1093/nar/gki964

Cited by 31 publications

(29 citation statements)

References 36 publications

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“…We have shown that on the PC1/3 promoter STAT3 and Nhlh2 interact as a heterodimer to mediate leptinstimulated PC1/3 expression. This is a novel mechanism for Nhlh2, which has previously been shown to interact with LMO2 or LMO3 at the E-box motif CAGCTG (29,30). Our results identify a new binding partner for Nhlh2 as well as a new E-box binding site of interaction (CAAATG).…”

Section: Discussionmentioning

confidence: 53%

Nescient Helix-Loop-Helix 2 Interacts with Signal Transducer and Activator of Transcription 3 to Regulate Transcription of Prohormone Convertase 1/3

Fox

Good

2008

Molecular Endocrinology

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Mechanisms controlling body weight involve gene regulation through the activation of signal transduction pathways. The Janus kinase/signal transducer and activator of transcription (STAT) signal transduction pathway is the mechanism primarily used by leptin in the hypothalamus. The transcription factor nescient helix-loop-helix 2 (Nhlh2) is a downstream target of leptin signaling and is expressed in proopiomelanocortin arcuate neurons. Proopiomelanocortin is cleaved by prohormone convertase 1/3 (PC1/3) to produce peptides that regulate the body's response to energy availability. Previous studies show that the PC1/3 promoter contains STAT3 sites mediating leptin-induced PC1/3 expression, and that Nhlh2 is required for hypothalamic PC1/3 expression because Nhlh2 knockout mice have reduced PC1/3 mRNA levels. Studies herein reveal that leptin-induced PC1/3 gene expression is abrogated in N2KO mice, and that in a hypothalamic cell line both STAT3 and Nhlh2 are required for the full transcriptional response of a PC1/3 reporter gene after leptin stimulation. Furthermore, it is shown that Nhlh2 binds to E-box motifs found adjacent to STAT3 sites in the PC1/3 promoter both in vitro and in chromatin immunoprecipitation assays. Finally, two different protein-protein interaction assays confirm the presence of a STAT3:Nhlh2 heterodimer on the PC1/3 promoter. The Nhlh2:STAT3 heterodimer may be an important transcriptional regulator of other hypothalamic genes in the leptin signaling pathway. These data confirm Nhlh2 as an integral element of the Janus kinase/STAT signaling pathway and are the first to demonstrate coordinated control of PC1/3 transcription by Nhlh2 and STAT3 after leptin stimulation.

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Section: Discussionmentioning

confidence: 53%

Nescient Helix-Loop-Helix 2 Interacts with Signal Transducer and Activator of Transcription 3 to Regulate Transcription of Prohormone Convertase 1/3

Fox

Good

2008

Molecular Endocrinology

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“…Human BEX2 was identified in fetal brain and a role in embryonic development has been suggested [24]. Expression was upregulated in MLL mutant AML cell lines compared to MLL wild-type AML cell lines suggesting a role in this particular type of hematological cancers.…”

Section: Bex Genes and Proteinsmentioning

confidence: 99%

“…Furthermore, mice deficient of BEX2 were viable and fertile under normal growth conditions and did not show any obvious phenotypic abnormalities [37]. Although BEX2 is apparently not involved in liver development, another study suggested that human BEX2, but not murine BEX1 or BEX2, associates with LIM-domain containing transcriptional factor (LMO2) [24], leading to enhancement of NSCL2-dependent transcriptional activity which is required for embryonal development.…”

Section: The Role Of Bex Proteins In Normal Cellsmentioning

confidence: 99%

Brain-Expressed X-linked (BEX) proteins in human cancers

Kazi

Kabir

2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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The Brain-Expressed X-linked (BEX) family proteins are comprised of five human proteins including BEX1, BEX2, BEX3, BEX4 and BEX5. BEX family proteins are expressed in a wide range of tissues and are known to play a role in neuronal development. Recent studies suggest a role of BEX family proteins in cancers. BEX1 expression is lost in a subgroup of patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Expression of BEX1 controls cell surface receptor signaling and restores imatinib response in resistant cells. BEX2 is overexpressed in a group of breast cancer patients and also in gliomas. Increased BEX2 expression led to enhanced NF-κB signaling as well as cell proliferation. Although BEX2 acts as tumor promoter in a subset of breast cancer, BEX3 expression displayed an opposite role. Overexpression of BEX3 resulted in inhibition of tumor formation in breast cancer mouse xenograft models. The role of BEX4 and BEX5 in cancer has not yet been defined. Collectively this suggests that BEX family members have distinct roles in cancers.While BEX1 and BEX3 act as a tumor suppressors, BEX2 seems to act as an oncogene.

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“…13 Unlike many other zinc fingers, the primary function of LIM domains is not to bind DNA, but to mediate interactions with other proteins. 14 LMO2 has been found to interact directly with a number of proteins including Tal1/SCL, GATA-1 and -2, 15 AF6, 16 retinoblastoma-binding protein 2, 17 Elf-2, 18 the neuronal proteins Bex2 and NSCL2, 19 and LIM domain-binding protein 1 (Ldb1/CLIM2/NLI). [20][21][22] LMO2 also participates in a number of multiprotein complexes that can localize to bipartite DNA sequences.…”

Section: Introductionmentioning

confidence: 99%