Acetylation of C/EBP alpha inhibits its granulopoietic function

CCAAT/enhancer-binding protein alpha (C/EBP alpha) is an essential transcription factor for myeloid lineage commitment. Here we demonstrate that acetylation of C/EBP alpha at lysine residues K298 and K302, mediated at least in part by general control non-derepressible 5 (GCN5), impairs C/EBP alpha DNA-binding ability and modulates C/EBP alpha transcriptional activity. Acetylated C/EBP alpha is enriched in human myeloid leukaemia cell lines and acute myeloid leukaemia (AML) samples, and downregulated upon granulocyte-colony stimulating factor (G-CSF)-mediated granulocytic differentiation of 32Dcl3 cells. C/EBP alpha mutants that mimic acetylation failed to induce granulocytic differentiation in C/EBP alpha-dependent assays, in both cell lines and in primary hematopoietic cells. Our data uncover GCN5 as a negative regulator of C/EBP alpha and demonstrate the importance of C/EBP alpha acetylation in myeloid differentiation

Sperm Motility Regulatory Proteins: A Tool to Enhance Sperm Quality

Sperm forward motility is an essential parameter in mammalian fertilization. Studies from our laboratory have identified and characterized a few unique sperm motility regulatory proteins/glycoproteins from the male reproductive fluids and mammalian blood serum. The purified sperm motility-initiating protein (MIP) from caprine epididymal plasma as well as the forward motility-stimulating factor (FMSF) and motility-stimulating protein (MSP) from buffalo and goat serum, respectively, have high efficacy to initiate or increase motility in nonmotile or less motile sperm. Antibody of sperm motility inhibitory factor (MIF-II) has the high potential to enhance sperm vertical velocity and forward motility by increasing intracellular cyclic adenosine monophosphate (cAMP) level. The appearance and disappearance of D-galactose–specific lectin and its receptor along the epididymis has been reported to be involved in motility regulation in spermatozoa. A novel synthetic cryopreservation method and role of lipid to protect membrane damage during cryopreservation have been demonstrated. Motility-promoting proteins may be extremely useful for improving cattle breeding and breeding of endangered species, thereby helping in enhanced production of animal products as well as in the conservation of animals. Isolated proteins and developed cryopreservation technology may also be beneficial in human infertility clinics to increase the chance of fertilization

The molecular mechanism of the aberrant expression of the B-cell specific PAX5 gene in t(8;21) AML

B-cell specific gene PAX5 (Busslinger, 2004) is aberrantly expressed in t(8;21) AML (Tiacci et al., 2004) and is potentially involved in blocking myeloid differentiation. To understand the mechanism of PAX5 deregulation in t(8;21) AML we examined the expression, chromatin structure, histone modifications and RNA Polymerase II recruitment at PAX5 in t(8;21) AML, in non-t(8;21) myeloid precursors and in a pre-B-cell-line. Our studies show that in non t(8;21) myeloid precursors, the PAX5 gene is poised for transcription but is repressed by polycomb complexes. This polycomb repression is alleviated in t(8;21) cells leading to PAX5 expression. t(8;21) AML model Kasumi-1 carries an activating C-KIT mutation that leads to constitutive activation of different downstream signalling pathways (Larizza et al., 2005). Some of these signalling pathways have been shown to regulate association of polycomb complexes with chromatin (Voncken et al., 2005). Our study shows that small molecule mediated inhibition of constitutively activated JNK, MEK and P38 signalling in Kasumi-1 cells lead to a down regulation of PAX5 expression, decrease in elongating RNA Polymerase II and H327ac with concomitant increase in H3K27me3 at PAX5. This suggests that deregulated MAPkinase signalling in t(8;21) AML leads to the dissociation of polycomb complexes from PAX5 causing its activation. It also suggests a novel role of tyrosine kinase mutations in lineage specification and differentiation block in t(8;21) AML

Tumorigenic de-differentiation: The Alternative splicing way.

Molecular & Cellular Oncology7061-

Lineage inappropriate PAX5 expression in t(8;21) acute myeloid leukemia requires signalling mediated abrogation of polycomb repression

Key Points Lineage-inappropriate expression of the B-cell master regulator PAX5 in t(8;21) AML depends on aberrant MAP kinase signaling. MAP kinase signaling by a mutated growth factor receptor leads to the dissociation of polycomb-repressive complexes from PAX5 chromatin.</jats:p

RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia

10.1038/s41388-020-01567-7ONCOGENE404746-76

Acetylation of C/EBPα inhibits its granulopoietic function

CCAAT/enhancer-binding protein alpha (C/EBPα) is an essential transcription factor for myeloid lineage commitment. Here we demonstrate that acetylation of C/EBPα at lysine residues K298 and K302, mediated at least in part by general control non-derepressible 5 (GCN5), impairs C/EBPα DNA-binding ability and modulates C/EBPα transcriptional activity. Acetylated C/EBPα is enriched in human myeloid leukaemia cell lines and acute myeloid leukaemia (AML) samples, and downregulated upon granulocyte-colony stimulating factor (G-CSF)- mediated granulocytic differentiation of 32Dcl3 cells. C/EBPα mutants that mimic acetylation failed to induce granulocytic differentiation in C/EBPα-dependent assays, in both cell lines and in primary hematopoietic cells. Our data uncover GCN5 as a negative regulator of C/EBPα and demonstrate the importance of C/EBPα acetylation in myeloid differentiation