Apoptosis in the hair follicle is programmed cell death, which occurs at a point during the cell cycle, when a sequence of programmed events causes the cells to be eliminated without the release of waste and harmful substances into the surrounding vicinity. Control of apoptosis is crucial to development of new and recycling of old cells within the body as over stimulation of apoptosis can be fatal, causing extreme tissue damage- examples of which are cancer sufferers. In this review we will discuss evidence from scientific experiments which investigate regulators of apoptosis and what really controls apoptosis in the hair follicle.
Apoptosis within the hair follicle cycle is controlled by many molecular processes and elements, of which include cytokines, tumor necrosis factor receptors, bcl-2 family gene products and ICE proteases (Soma et al., 1998). Apoptosis occurs during the catagen stage of follicle cycling which can also be known as the regression stage, and begins with initiation of receptors to their binding sites. This is specifically the binding of receptors that are rich in extracellular cysteine usually needed for binding, and intracellular compartments specific for signalling (Botchkareva et al., 2006). These receptors- also known as death receptors initiate the beginning of apoptosis, signalling via the mitochondrial membrane and setting in motion adapter molecules complementary to their apoptotic receptors (APO1/Fas receptor or tumor necrosis factor receptor- TNFR). Others include tyrosine kinase receptors- such as nerve growth factor (NGF), and p75 receptor- ‘p75NTR signalling is critically important for apoptosis in the regressing ORS and, therefore, for its shortening during catagen’ ( Botchkarev et al.,2000). These signals are conveyed into the cell via a cascade of enzymes known as caspases, which subsequently lead to the next stages of apoptosis.
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Investigations into apoptosis show that ‘physiological and pathological catagen is noticeably characterised by an up-regulation of ICE expression and an apparent inversion of the Bcl-2/Bax ratio in all epithelial follicle regions that undergo involution during catagen.’(Linder et al., 1997) This refers to intracellular and extracellular molecules located around the hair follicle, which show some control of the progression of cell death, when subjected to variation. The investigation proved that apoptosis within follicular keratinocytes in a normal state or diseased state occurred after a significant reduction in the Bcl-2/Bax ratio, which in turn caused activation of ICE proteases and eventually activation of endonucleases (Linder et al., 1997). This indicates that Bcl-2 and Bax ratios to an extent control apoptosis when down regulated, and then cause a domino effect to upregulate ICE proteases known as the caspase family, to eventually cause DNA to be cleaved into smaller fragments, cell shrinkage and rounding, breakdown of the cytoskeleton and membrane blebbing.
Caspases are the final inducer of apoptosis from physiological or pathological stimulation, and therefore play a major role in control of apoptosis, by remaining as an inactive form when apoptosis is not required, but becoming activated by the down regulation of the Bcl-2/Bax family of receptors, when apoptosis is required to take place. Caspases are mediators of apoptosis, and are defined and separated into two groups. The first group are the ‘instigators’ and begin the cascade, the second group are the ‘terminators’ which are activated by the instigators and cause the activation of other enzymes within the cell. The caspase family consists of caspase-8, caspase-10 and caspase-3, which act to activate the intrinsic pathway, and to link the extrinsic to the intrinsic pathway by releasing cytochrome c, a process which is primarily controlled by a family of proteins known as the Bcl-2 proteins. These are expressed in the epithelium, surrounding mesenchyme, and follicular papilla of the adult hair follicle throughout the cycle (Stenn et al., 1994).
The release of cytochrome c ultimately forms a holoenzyme known as the apotosome, which is formed by the apoptosis initiator enzyme procaspase-9, and its adaptor molecule Apaf-1(Botchkareva et al., 2006). These apoptosomes then cleave and activate the procaspase into caspase-9, which subsequently turns on effector caspase-3. Caspase-3 is a major proteolytic enzyme, with the ability to defragment a wide range of molecules and substrates within the cell. The activation of caspase-3 then leads to the cell fragmentation and phagocytosis stages of hair follicle apoptosis.
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