Philadelphia Chromosome (PH)
(Philadelphia Translocation, PH and Chronic Myeloid Leukemia – CML)
Translocation is a Structural Aberration of Chromosome
Translocation is a type of structural aberration of the chromosome where a segment of chromosome gets translocated to another chromosome. There may be two types of translocation based on the nature of the exchange. They are:
(1). Homologous Translocation
(2). Heterologous Translocation
In homologous translocation, the exchange of chromosomal segments occurs between the homologous chromosomes. In heterologous translocation, the chromosomal segments are exchanged between non-homologous chromosomes. The heterologous translocation in most of the cases will be a reciprocal translocation (exchange of segments between chromosomes).
Translocation causes ‘Position Effect’
The translocation of chromosomes leads to a phenomenon in molecular genetics called the ‘Position Effect’. The position effect is the change in the expression pattern of a gene due to its current position in the chromosome. For example, a normally active gene may be converted to an inactive gene when it is translocated into a new position or vice versa.
Extrinsic Pathway of Apoptosis
(The Receptor-Mediated Programmed Cell Death Pathway)
In the extrinsic pathway of apoptosis, the death-inducing signal for the programmed cell death is triggered by an external stimulus. For receiving such an external death-inducing signal, the cell possesses plasma membrane receptors specific to each stimulus and thus the extrinsic signalling of apoptosis is also known as the Receptor Mediated programmed cell death pathway.
The external stimuli for the apoptosis in most of the cases will be a cytokine. The most studied cytokine to induce extrinsic pathway of apoptosis is an extracellular messenger protein called Tumor Necrosis Factor (TNF). TNF is so named because it was first discovered as a protein factor which induces cell death in cancerous cells. The TNF cytokine is produced by the cells of the immune system in response towards the adverse conditions. The adverse conditions that can provoke the immune cells to produce TNF are:
Ø Exposure to radiation
Ø Introduction of viral toxins
Ø Exposure to elevated temperature
Ø Exposure to other toxic substances
The detailed signaling mechanism of TNF-mediated extrinsic pathway of apoptosis is summarized below:
Ø TNF first binds to its receptor called TNFR1 (Tumor Necrosis Factor Receptor-1) present on the plasma membrane.
Ø TNFR1 is a member of death receptor family proteins that turn on the apoptotic cell death process in eukaryotic cells.
Ø TNFR1 is a trans-membrane receptor with an external ligand binding domain and a cytosolic domain.