Disease relevance of MLL2

• The product of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene, menin, is an integral component of MLL1/MLL2 histone methyltransferase complexes specific for Lys4 of histone H3 (H3K4) [1].
• The validity of this approach is supported by the detection of nervous system-specific genes (e.g., glial fibrillary acid protein) and genes known to show trinucleotide expansions in disease (e.g., AAD10 associated with spino cerebellar ataxia type 2) [2].

High impact information on MLL2

• The analysis of ALR expression showed that its approximately 18 kb long mRNA is expressed, like ALL-1, in most adult tissues, including a variety of hematopoietic cells, with the exception of the liver [3].
• The ALR gene was mapped to chromosome band 12q12-13, adjacent to the VDR gene [3].
• We have cloned a novel human gene, ALR, which encodes a gigantic 5262 amino acid long protein containing a SET domain, five PHD fingers, potential zinc fingers, and a very long run of glutamines interrupted by hydrophobic residues, mostly leucine [3].
• The MLL2 gene was expressed in three cases with HBV DNA integrated into exon 3 of MLL2 and in one case with HBV DNA integrated into intron 3 of MLL2 [4].
• Eight protein-coding regions were involved: ras-responsive element binding protein 1, calmodulin 1, mixed lineage leukemia 2 (MLL2), FLJ333655, LOC220272, LOC255345, LOC220220, and LOC168991 [4].

Biological context of MLL2

• Gene expression analysis suggested that two HCCs with HBV integrated into MLL2 had similar patterns of gene expression compared with three HCCs with HBV integrated into other loci of human chromosomes [4].
• Different stages of liver regeneration are regulated by a variety of factors such as the liver growth associated protein ALR, augmenter of liver regeneration [5].
• Eukaryotic homologs of CorA, although clearly functional as Mg2+ transporters, have minimal sequence homology and include the Mrs2p mitochondrial Mg2+ channel and the ALR proteins of fungi [6].

Anatomical context of MLL2

• Therefore, using primary human hepatocytes in vitro we investigated the effect of ALR on the biosynthesis of polyamines [5].
• This combination of ribosome display and immobilized model membranes was effective as an in vitro high-throughput screening system and enabled us to identify motif sequences (ALR, KVL) that selectively recognized the bacterial membrane [7].

Associations of MLL2 with chemical compounds

• We demonstrated by HPLC analysis that recombinant ALR enhanced intracellular hepatic putrescine, spermidine, and spermine levels within 9-12h [5].
• Additionally, ALR treatment induced mRNA expression of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase, both key enzymes of polyamine biosynthesis [5].

Physical interactions of MLL2

• Recruitment of the MLL2 complex to the beta-globin locus is dependent upon NF-E2 and coincides spatio-temporally with NF-E2 binding during erythroid differentiation [8].

Other interactions of MLL2

• Phosphorylation-defective mutants of either or both of these residues retain the associated histone methyltransferase activity of menin, as well as binding to the trithorax complex members Ash2L, Rbbp5, and MLL2 and to RNA polymerase II [9].

References