Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Gene Review:

MLL4 - myeloid/lymphoid or mixed-lineage leukemia 4

Homo sapiens

Synonyms: HRX2, Histone-lysine N-methyltransferase MLL4, KIAA0304, KMT2D, Lysine N-methyltransferase 2D, ...

Tanaka, T. et al., Huntsman, D.G. et al., Hansen, J.M. et al., Lee, S. et al., Wang, D. et al., et al.

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Disease relevance of MLL4

We find that MLL2 is amplified in two of 14 pancreatic carcinoma cell lines and one of five glioblastoma cell lines and is a likely critical gene in 19q13.1 amplifications [1].
A homolog of MLL denoted MLL2, which represents the second human homolog of the Drosophila trithorax gene, was characterized by assembling ESTs, the KIAA0304 cDNA clone, RT - PCR fragments and a new clone isolated from a cDNA phage library and compared to the available genomic sequence [1].

High impact information on MLL4

Taspase1 deficiency incurs down-regulation of Cyclin Es, As, and Bs and up-regulation of p16(Ink4a) . We show that MLL and MLL2 directly target E2Fs for Cyclin expression [2].
Here we show that TRX-2 is an essential gene and that Trx-2-deficient cells undergo apoptosis upon repression of the TRX-2 transgene, showing an accumulation of intracellular reactive oxygen species (ROS) [3].
To investigate the biological significance of Trx-2, we cloned chicken TRX-2 cDNA and generated clones of the conditional Trx-2-deficient cells using chicken B-cell line, DT40 [3].
Cytochrome c is released from mitochondria, while caspase-9 and caspase-3, but not caspase-8, are activated upon inhibition of the TRX-2 transgene [3].
These results suggest that ASC-2 confers target gene specificity to MLL3 and MLL4 H3K4MT complexes and that recruitment of H3K4MTs to their target genes generally involves interactions between integral components of H3K4MT complexes and transcription factors [4].

Biological context of MLL4

MLL2 encodes a protein that exhibits a high level of similarity to MLL over several important protein domains [5].
Thioredoxin-2 (TRX-2) is an essential gene regulating mitochondria-dependent apoptosis [3].
Production of ATP was not significantly changed by down-regulation of Trx2 expression [6].
In addition, MCF-7 cell growth was also inhibited by the depletion of MLL2 [7].
These findings indicate a link between the redox active site cysteine-independent action of TRX2 and the level of Bcl-xL in the regulation of apoptosis [6].

Associations of MLL4 with chemical compounds

The MLL2 complex was recruited on promoters of ERalpha target genes along with ERalpha upon estrogen stimulation [7].
The magnitude of effects of arsenic, cadmium, and mercury was greater for the mitochondrial Trx2 (>60 mV) compared to the cytoplasmic Trx1 (20 to 40 mV) [8].
GSH/GSSG redox states were determined by HPLC, and Trx1 and Trx2 redox states were determined by Redox Western blot methods [8].

References

MLL2, the second human homolog of the Drosophila trithorax gene, maps to 19q13.1 and is amplified in solid tumor cell lines. Huntsman, D.G., Chin, S.F., Muleris, M., Batley, S.J., Collins, V.P., Wiedemann, L.M., Aparicio, S., Caldas, C. Oncogene (1999) [Pubmed]
Proteolysis of MLL family proteins is essential for Taspase1-orchestrated cell cycle progression. Takeda, S., Chen, D.Y., Westergard, T.D., Fisher, J.K., Rubens, J.A., Sasagawa, S., Kan, J.T., Korsmeyer, S.J., Cheng, E.H., Hsieh, J.J. Genes Dev. (2006) [Pubmed]
Thioredoxin-2 (TRX-2) is an essential gene regulating mitochondria-dependent apoptosis. Tanaka, T., Hosoi, F., Yamaguchi-Iwai, Y., Nakamura, H., Masutani, H., Ueda, S., Nishiyama, A., Takeda, S., Wada, H., Spyrou, G., Yodoi, J. EMBO J. (2002) [Pubmed]
Coactivator as a target gene specificity determinant for histone H3 lysine 4 methyltransferases. Lee, S., Lee, D.K., Dou, Y., Lee, J., Lee, B., Kwak, E., Kong, Y.Y., Lee, S.K., Roeder, R.G., Lee, J.W. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
MLL2: A new mammalian member of the trx/MLL family of genes. FitzGerald, K.T., Diaz, M.O. Genomics (1999) [Pubmed]
Control of mitochondrial outer membrane permeabilization and Bcl-xL levels by thioredoxin 2 in DT40 cells. Wang, D., Masutani, H., Oka, S., Tanaka, T., Yamaguchi-Iwai, Y., Nakamura, H., Yodoi, J. J. Biol. Chem. (2006) [Pubmed]
Identification of the MLL2 complex as a coactivator for estrogen receptor alpha. Mo, R., Rao, S.M., Zhu, Y.J. J. Biol. Chem. (2006) [Pubmed]
Differential oxidation of thioredoxin-1, thioredoxin-2, and glutathione by metal ions. Hansen, J.M., Zhang, H., Jones, D.P. Free Radic. Biol. Med. (2006) [Pubmed]

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