Role of a Chimeric Transcription Factor in Acute Promyelocytic Leukemia

“GROUP 7” ROLL NO: 19,20,24

Chimeric protein

• Fusion proteins or chimeric proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this fusion gene results in a single or multiple polypeptides with functional properties derived from each of the original proteins.

• Acute promyelocytic leukemia is a subtype of acute myelogenous leukemia (AML), a cancer of the white blood cells.

• There is a defect in the gene & its transcription factor so promylocyte cannot differentiate into granulocyte

RAR alpha/RXR transcription factor is required for the differentiation of …

NORMAL CONDITION • Correct regulation of gene expression involves both

transcription factors and the DNA regulatory elements to which they bind.

• LETS GO DEEPER TO UNDERSTAND BETTER Gene expression: For the maturation of WBC you

need some protein, so hematopoietic stem cells in bone marrow receive the stimulus to produce the protein required for that differentiation of WBC, we know that the codes for particular protein is present in DNA which is present in chromosomes inside the nucleus.

• In human body there are 46 chromosomes in all cells inside nucleus

• The difference between all these cells is that ,only a particular group of cell in a particular organ can produce a particular protein which may be enzymes or hormones..etc

• In hematopoietic stem cell there are 46 number of chromosomes. In each cell only one chromosome (and its DNA) inside nucleus has the code to produce the protein required for that differentiation of WBC.

• Now rna-polymerase finds the DNA sequence for that protein present only in one of the 46 chromosomes (within the DNA), and transcripts its codes.

Transcription

• Now the m-rna produced inside the nucleus it goes out through the nuclear pore then to ER then translation occurs and finally produces protein

• but the basic thing we need to remember here is that the rna- polymerase which is needed for the production of m-rna cannot bind to the DNA directly.

• But it needs some transcription factors for its binding. These transcription factors bind to the flanking regions which contain the sequences for regulation of gene transcription called Regulatory elements.

• So far we saw about the importance of the TF• Abnormalities of transcriptional factor or regulatory

elements result in abnormal regulation of gene expression, which is often manifested as disease.

• An example of a transcription factor abnormality is acute promyelocytic leukemia (APL)

• It is a cancer of the white blood cells. In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes.

• Normal differentiation of wbc requires RARα protein controls the activity (transcription) of genes that are important for the maturation (differentiation) of immature white blood cells beyond a particular stage called the promyelocyte

• The RARA gene provides instructions for making a transcription factor called the retinoic acid receptor, alpha (RARα).

• RARA is present in 17th chromosome.• In this disease there is a translocation of PML gene located

on 15th chromosome to the 17th chromosome• A rearrangement (translocation) of genetic material

between chromosomes 15 and 17, written as t(15;17), fuses part of the PML gene on chromosome 15 with part of another gene on chromosome 17 called RARA.

• The protein produced from this fused gene, PML-RARα, functions differently than the protein products of the normal PML and RARA genes.

• Normally retinoic acid binds with retinoic acid receptor, alpha (RARα).

• During the first step in protein production. The RARα/RXR protein binds to specific regions of DNA and attracts other proteins that help block (repress) gene transcription. but, In response to a specific signal, (retinoic acid) the repressive proteins N-CoR are removed and other proteins that induce gene transcription bind to the RARα protein, allowing gene transcription and cell differentiation.

• RARα forms heterodimers with retinoid X receptor (RXR) and binds to retinoic acid response elements (RAREs) that are present in genes (chromosome no 17) involved in cell differentiation.

• In the absence of RA, RARα/RXR heterodimers bind to RAREs and recruit (strengthen) the corepressor N-CoR, which in turn recruits (strengthen) HDACs that inhibit gene transcription.

• Histone deacetylases are a class of enzymes that remove acetyl groups ( acetyl group help loosening of DNA) from an N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly thus inhibiting transcription.

• Binding of RA to RARα leads to dissociation of N-CoR, which permits binding of the CBP coactivator and activation of RARα-responsive genes that promote cell differentiation

• Acute promyelocytic leukemia is characterized by a chromosomal translocation involving the retinoic acid receptor-alpha gene on chromosome 17 (RARA). In 95% of cases of APL, retinoic acid receptor-alpha (RARA) gene on chromosome 17 is involved in a reciprocal translocation with the promyelocytic leukemia gene (PML) on chromosome 15.

• A rearrangement (translocation) of genetic material between chromosomes 15 and 17, written as t(15;17), fuses part of the PML gene on chromosome 15 with part of another gene on chromosome 17 called RARA. The protein produced from this fused gene, PML-RARα, functions differently than the protein products of the normal PML and RARA genes.

• The protein produced from this fused gene, the PML-RARα protein, functions differently than the protein products of the normal PML and RARA genes.

• The PML-RARα protein binds retenoic acid and forms heterodimers with RXR.

• This complex binds to DNA and represses gene transcription, like the normal RARα protein. However, the PML-RARα protein does not respond to the signal (retenoic acid) to induce transcription of genes, so the genes remain repressed.

Molecular actions of the PML-RARa fusion protein in promyelocytic leukaemia.mp4

• PML-RARα also binds with retenoic acid but does not dissociate N-CoR when retenoic acid binds to it which in turn strengthens histone deacytalase and inhibits transcription.

• At physiological levels of RA, N-CoR remains bound to PML/RARalpha, blocking promyelocytic differentiation. However, high concentrations of RA induce dissociation of N-CoR and permit differentiation. This mechanism explains why high concentrations of exogenous RA can be used to induce clinical remissions in patients with APL.

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