Tag Content
SG ID
SG00016918 
UniProt Accession
Theoretical PI
9.34  
Molecular Weight
30432 Da  
Genbank Nucleotide ID
Genbank Protein ID
Gene Name
Mlf1 
Gene Synonyms/Alias
Hls7 
Protein Name
Myeloid leukemia factor 1 
Protein Synonyms/Alias
Hematopoietic lineage switch 7; Myelodysplasia-myeloid leukemia factor 1; 
Organism
Mus musculus (Mouse) 
NCBI Taxonomy ID
10090 
Chromosome Location
chr:3;67178019-67203925;1
View in Ensembl genome browser  
Function in Stage
Uncertain 
Function in Cell Type
Uncertain 
Probability (GAS) of Function in Spermatogenesis
0.875194122 
The probability was calculated by GAS algorithm, ranging from 0 to 1. The closer it is to 1, the more possibly it functions in spermatogenesis.
Description
Temporarily unavailable 
Abstract of related literatures
1. The NPM-MLF1 fusion protein is expressed in blasts from patients with myelodysplasia/acute myeloid leukemia (MDS/AML) containing the t(3;5) chromosomal rearrangement. Nucleophosmin (NPM), a previously characterized nucleolar phosphoprotein, contributes to two other fusion proteins found in lympho-hematopoietic malignancies, anaplastic large cell lymphoma (NPM-ALK) and acute promyelocytic leukemia (NPM-RARalpha). By contrast, the function of the carboxy-terminal fusion partner, myelodysplasia/myeloid leukemia factor 1 (MLF1), is unknown. To aid in understanding normal MLF1 function, we isolated the murine cDNA, determined the chromosomal localization of Mlf1, and defined its tissue expression by in situ hybridization. Mlf1 was highly similar to its human homologue (86% and 84% identical nucleotide and amino acid sequence, respectively) and mapped to the central region of chromosome 3, within a segment lacking known mouse mutations. Mlf1 tissue distribution was restricted during both development and postnatal life, with high levels present only in skeletal, cardiac, and selected smooth muscle, gonadal tissues, and rare epithelial tissues including the nasal mucosa and the ependyma/choroid plexus in the brain. Mlf1 transcripts were undetectable in the lympho-hematopoietic organs of both the embryonic and adult mouse, suggesting that NPM-MLF1 contributes to the genesis of MDS/AML in part by enforcing the ectopic overexpression of MLF1 within hematopoietic tissues. PMID: [10393836] 

2. Hemopoietic lineage switching occurs when leukemic cells, apparently committed to one lineage, change and display the phenotype of another pathway. cDNA representational difference analysis was used to identify myeloid-specific genes that may be associated with an erythroid to myeloid lineage switch involving the murine J2E erythroleukemic cell line. One of the genes isolated (HLS7) is homologous to the novel human oncogene myeloid leukemia factor 1 (MLF1) involved in the t(3;5)(q25.1;q34) translocation associated with acute myeloid leukemia. Enforced expression of HLS7 in J2E cells induced a monoblastoid phenotype, thereby recapitulating the spontaneous erythroid to myeloid lineage switch. HLS7 also inhibited erythropoietin- or chemically-induced differentiation of erythroleukemic cell lines and suppressed development of erythropoietin-responsive colonies in semi-solid culture. However, intracellular signaling activated by erythropoietin was not impeded by ectopic expression of HLS7. In contrast, HLS7 promoted maturation of M1 monoblastoid cells and increased myeloid colony formation in vitro. These data show that HLS7 can influence erythroid/myeloid lineage switching and the development of normal hemopoietic cells. PMID: [10523300] 

3. A yeast two-hybrid screen was conducted to identify binding partners of Mlf1, an oncoprotein recently identified in a translocation with nucleophosmin that causes acute myeloid leukemia. Two proteins isolated in this screen were 14-3-3zeta and a novel adaptor, Madm. Mlf1 contains a classic RSXSXP sequence for 14-3-3 binding and is associated with 14-3-3zeta via this phosphorylated motif. Madm co-immunoprecipitated with Mlf1 and co-localized in the cytoplasm. In addition, Madm recruited a serine kinase, which phosphorylated both Madm and Mlf1 including the RSXSXP motif. In contrast to wild-type Mlf1, the oncogenic fusion protein nucleophosmin (NPM)-MLF1 did not bind 14-3-3zeta, had altered Madm binding, and localized exclusively in the nucleus. Ectopic expression of Madm in M1 myeloid cells suppressed cytokine-induced differentiation unlike Mlf1, which promotes maturation. Because the Mlf1 binding region of Madm and its own dimerization domain overlapped, the levels of Madm and Mlf1 may affect complex formation and regulate differentiation. In summary, this study has identified two partner proteins of Mlf1 that may influence its subcellular localization and biological function. PMID: [12176995] 

4. Myeloid leukemia factor 1 (MLF1) is a novel oncoprotein involved in translocations associated with acute myeloid leukemia (AML), especially erythroleukemias. In this study, we demonstrate that ectopic expression of Mlf1 prevented J2E erythroleukemic cells from undergoing biological and morphological maturation in response to erythropoietin (Epo). We show that Mlf1 inhibited Epo-induced cell cycle exit and suppressed a rise in the cell cycle inhibitor p27(Kip1). Unlike differentiating J2E cells, Mlf1-expressing cells did not downregulate Cul1 and Skp2, components of the ubiquitin E3 ligase complex SCF(Skp2) involved in the proteasomal degradation of p27(Kip1). In contrast, Mlf1 did not interfere with increases in p27(Kip1) and terminal differentiation initiated by thyroid hormone withdrawal from erythroid cells, or cytokine-stimulated maturation of myeloid cells. These data demonstrate that Mlf1 interferes with an Epo-responsive pathway involving p27(Kip1) accumulation, which inhibits cell cycle arrest essential for erythroid terminal differentiation. PMID: [15122318] 

5. Myeloid leukemia factor 1 (MLF1) is an oncoprotein associated with hemopoietic lineage commitment and acute myeloid leukemia. Here we show that Mlf1 associated with a novel binding partner, Mlf1-associated nuclear protein (Manp), a new heterogeneous nuclear ribonucleoprotein (hnRNP) family member, related to hnRNP-U. Manp localized exclusively in the nucleus and could redirect Mlf1 from the cytoplasm into the nucleus. The nuclear content of Mlf1 was also regulated by 14-3-3 binding to a canonical 14-3-3 binding motif within the N terminus of Mlf1. Significantly Mlf1 contains a functional nuclear export signal and localized primarily to the nuclei of hemopoietic cells. Mlf1 was capable of binding DNA, and microarray analysis revealed that it affected the expression of several genes, including transcription factors. In summary, this study reveals that Mlf1 translocates between nucleus and cytoplasm, associates with a novel hnRNP, and influences gene expression. PMID: [17008314] 

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Function
Involved in lineage commitment of primary hemopoieticprogenitors by restricting erythroid formation and enhancingmyeloid formation. Interferes with erythropoietin-inducederythroid terminal differentiation by preventing cells fromexiting the cell cycle through suppression of CDKN1B/p27Kip1levels. Suppresses RFWD2/COP1 activity via CSN3 which activatesp53 and induces cell cycle arrest. Binds DNA and affects theexpression of a number of genes so may function as a transcriptionfactor in the nucleus. 
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Subcellular Location
Cytoplasm. Nucleus. Note=In non-hematopoietic cells, resides primarily in the cytoplasm with somepunctate nuclear localization. Shuttles between the cytoplasm andnucleus. In hematopoietic cells, located preferentially in thenucleus. 
Tissue Specificity
Highly expressed in skeletal muscle, heart,testis. Also found in lung, but not in spleen, thymus, bonemarrow, liver and kidney. 
Gene Ontology
GO IDGO termEvidence
GO:0005737 C:cytoplasm IDA:UniProtKB.
GO:0005634 C:nucleus IDA:UniProtKB.
GO:0003677 F:DNA binding IDA:UniProtKB.
GO:0007050 P:cell cycle arrest ISS:UniProtKB.
GO:0002318 P:myeloid progenitor cell differentiation IDA:UniProtKB.
GO:0006351 P:transcription, DNA-dependent IDA:UniProtKB.
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Interpro
IPR019376;    Myeloid_leukemia_factor.
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Pfam
PF10248;    Mlf1IP;    1.
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SMART
PROSITE
PRINTS
Created Date
18-Oct-2012 
Record Type
GAS predicted 
Sequence Annotation
CHAIN         1    267       Myeloid leukemia factor 1.
                             /FTId=PRO_0000220753.
REGION       50    125       Interaction with COPS3 (By similarity).
MOD_RES      34     34       Phosphoserine (By similarity).
MUTAGEN      34     34       S->A: 70% reduction in binding to YWHAZ
                             and increased nuclear localization.
MUTAGEN     149    149       S->A: No effect on binding to YWHAZ.
CONFLICT    172    172       N -> Y (in Ref. 2; AAC17946).
CONFLICT    214    214       N -> H (in Ref. 2; AAC17946).
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Nucleotide Sequence
Length: 879 bp   Go to nucleotide: FASTA
Protein Sequence
Length: 267 bp   Go to amino acid: FASTA
The verified Protein-Protein interaction information
UniProt
Gene Symbol Ref Databases
YwhazIntAct 
Eif3gIntAct 
YwhazBioGRID 
CacybpIntAct 
Dynll2IntAct 
Nrbp1BioGRID 
Nrbp1IntAct 
NclIntAct 
Other Protein-Protein interaction resources
String database  
View Microarray data
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