Reactome | Transcriptional Regulation by VENTX

Transcriptional Regulation by VENTX

Stable Identifier

R-HSA-8853884

Type

Pathway

Species

Homo sapiens

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The VENTX (also known as VENT homeobox or VENTX2) gene is a member of the homeobox family of transcription factors. The ortholog of VENTX was first described in Xenopus where it participates in BMP and Nanog signaling pathways and controls dorsoventral mesoderm patterning (Onichtchouk et al. 1996, Scerbo et al. 2012). The zebrafish ortholog of VENTX is also involved in dorsoventral patterning in the early embryo (Imai et al. 2001). Rodents lack the VENTX ortholog (Zhong and Holland 2011). VENTX is expressed in human blood cells (Moretti et al. 2001) and appears to play an important role in hematopoiesis. The role of VENTX in hematopoiesis was first suggested based on its role in mesoderm patterning in Xenopus and zebrafish (Davidson and Zon 2000). VENTX promotes cell cycle arrest and differentiation of hematopoietic stem cells and/or progenitor cells (Wu, Gao, Ke, Giese and Zhu 2011, Wu et al. 2014). Ventx suppression leads to expansion of hematopoietic stem cells and multi-progenitor cells (Gao et, J. Biol.Chem, 2012). VENTX induces transcription of cell cycle inhibitors TP53 (p53) and p16INK4A and activates tumor suppressor pathways regulated by TP53 and p16INK4A (Wu, Gao, Ke, Hager et al. 2011), as well as macrophage colony stimulating factor receptor (CSF1R) (Wu, Gao, Ke, Giese and Zhu 2011) and inhibits transcription of cyclin D1 (CCND1) (Gao et al. 2010) and Interleukin-6 (IL6) (Wu et al. 2014). Chromatin immunoprecipitation showed that EGR3 transcription factor directly binds to the promoter of IL6 and IL8 genes (Baron VT et al, BJC 2015). While VENTX expression may suppress lymphocytic leukemia (Gao et al. 2010), high levels of VENTX have been reported in acute myeloid leukemia cells, with a positive effect on their proliferation (Rawat et al. 2010). Another homeobox transcription factor that regulates differentiation of hematopoietic stemm cells is DLX4 (Bon et al. 2015). Studies on colon cancer showed that VentX regulates tumor associated macrophages and reverts immune suppression in tumor microenvironment (Le et al. 2018). MEK1 is required for Xenopus Ventx2 asymmetric distribution during blastula cell division. Ventx2 inhibition by MEK1 is required for embryonic cell commitment (Scerbo et al, eLife, 2017). VENTX induces TP53-independent apoptosis in cancer cells (Gao H, Oncotarget, 2016). During Xenopus embryonic development, VENTX ortholog regulates transcription of the sox3 gene (Rogers et al. 2007) as well as the early neuronal gene zic3 (Umair et al. 2018).

Literature References

PubMed ID	Title	Journal	Year
20028861	VentX, a novel lymphoid-enhancing factor/T-cell factor-associated transcription repressor, is a putative tumor suppressor Le, Y, Silberstein, LE, Giese, RW, Gao, H, Wu, X, Zhu, Z	Cancer Res.	2010
22606298	Ventx factors function as Nanog-like guardians of developmental potential in Xenopus Coen, L, Kodjabachian, L, Scerbo, P, Luxardi, G, Markov, GV, Girardot, F, Vivien, C, Demeneix, B	PLoS ONE	2012
24706756	Homeobox transcription factor VentX regulates differentiation and maturation of human dendritic cells Gao, H, Wu, X, Zhu, Z, Bleday, R	J. Biol. Chem.	2014
25633035	Early Growth Response 3 regulates genes of inflammation and directly activates IL6 and IL8 expression in prostate cancer Mercola, D, Jia, Z, Pio, R, Baron, VT	Br. J. Cancer	2015
27175592	Homeobox protein VentX induces p53-independent apoptosis in cancer cells Wu, B, Le, Y, Gao, H, Zhu, Z	Oncotarget	2016
26208636	The homeobox gene DLX4 regulates erythro-megakaryocytic differentiation by stimulating IL-1β and NF-κB signaling Zweidler-McKay, PA, Barengo, N, Lee, JS, Trinh, BQ, Naora, H, Kim, SB	J. Cell. Sci.	2015
21670496	The homeobox transcription factor VentX controls human macrophage terminal differentiation and proinflammatory activation Giese, RW, Ke, W, Gao, H, Wu, X, Zhu, Z	J. Clin. Invest.	2011
21679462	The dynamics of vertebrate homeobox gene evolution: gain and loss of genes in mouse and human lineages Holland, PW, Zhong, YF	BMC Evol. Biol.	2011
20833819	The vent-like homeobox gene VENTX promotes human myeloid differentiation and is highly expressed in acute myeloid leukemia D'Andrea, RJ, Rawat, VP, Buske, C, Thoene, S, Arseni, N, Bohlander, SK, Hiddemann, W, Mulaw, MA, Sadlon, T, Heilmeier, B, Feuring-Buske, M, Ahmed, F	Proc. Natl. Acad. Sci. U.S.A.	2010
29872044	The homeobox protein VentX reverts immune suppression in the tumor microenvironment Le, Y, Gao, H, Zhu, Z, Bleday, R	Nat Commun	2018
10948449	Turning mesoderm into blood: the formation of hematopoietic stem cells during embryogenesis Zon, LI, Davidson, AJ	Curr. Top. Dev. Biol.	2000
11493559	The homeobox genes vox and vent are redundant repressors of dorsal fates in zebrafish Schier, AF, Talbot, WS, Gates, MA, Melby, AE, Kimelman, D, Imai, Y	Development	2001
8898218	The Xvent-2 homeobox gene is part of the BMP-4 signalling pathway controlling [correction of controling] dorsoventral patterning of Xenopus mesoderm Dosch, R, Onichtchouk, D, Delius, H, Gawantka, V, Niehrs, C, Blumenstock, C, Hirschfeld, K	Development	1996
11549314	Molecular cloning of a human Vent-like homeobox gene Zon, LI, Lilley, B, Baker, E, D'Andrea, RJ, Moretti, PA, Davidson, AJ	Genomics	2001
18031719	Sox3 expression is maintained by FGF signaling and restricted to the neural plate by Vent proteins in the Xenopus embryo Grammer, TC, Cunningham, DD, Casey, EM, Archer, TC, Rogers, CD	Dev. Biol.	2008
21325273	VentX trans-activates p53 and p16ink4a to regulate cellular senescence Hager, M, Freeman, MR, Xiao, S, Ke, W, Gao, H, Wu, X, Zhu, Z	J. Biol. Chem.	2011
30590909	Ventx1.1 as a Direct Repressor of Early Neural Gene zic3 in Xenopus laevis Kim, J, Kumar, V, Umair, Z, Kim, S, Lee, JY, Kim, DH, Kumar, S, Park, JB, Lee, U, Rafiq, K	Mol. Cells	2018
28654420	Lineage commitment of embryonic cells involves MEK1-dependent clearance of pluripotency regulator Ventx2 Marchal, L, Kodjabachian, L, Scerbo, P	Elife	2017