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Few gene families regulate apoptosis, taking part in normal cell proliferation and differentiation as well. Cell oncogenes c-fos, c-myc, c-bcl-2 are among them. But their expression leads to apoptosis only with simultaneous coexpression of p-53 anti-oncogene. In cells of nematode Caenorhabditis elegans gene family consisted of ced-3, ced-4, ced-9 was defined. This group was called apoptosome. In mammalians it correlates with caspase-9, apaf-1, bcl-2/xL, which are taking part together in cell suicide. However, single activation of ced-9 or bcl-2 leads to cell proliferation without self-destruction [8].
In certain conditions apoptosis is initiated by growth factors, which are proliferative agents as well. Glucocorticoids are also inductors of apoptosis, in spite of their prosperities to protein synthesis. Glucocorticoids are able to rebuild chromatin in nuclease-sensitive conformation. Simultaneously poly (ADP-rybosyl)ation begins. This modificative reaction induces DNA reparation. This situation can be realized only when chromatin is totally decondensated (as observed by electronic microscopy). It allows easy access of proteases to link sites of DNA molecule and permits nucleosomic destruction of DNA. During apoptosis in tumor cells transcriptional activation of long DNA repeats occurs. In apoptotic cells about 70% of splinted DNA fragments are transcriptional active ribosomal genes. Increasing of DNA-polymerase-II activity and intensive synthesis of DNA, RNA and protein accompany apoptosis. Inhibitors of protein synthesis prevent apoptosis, but controversially can be caused by them. Phosphatidyl-inosylating system of transmembrane signal transduction is also acting during apoptosis. This system is known to take part in mitosis as well. During this process changes in protein kinase C, CD3/T and IL2R/IL2 receptor complexes, Ca++ concentration, phosphorylation occurs. Interaction between monoclonal antibodies and CD3/T receptor, which is known as activation antigen, leads to apoptosis. During apoptotic process activity of transglutaminase also increase [16]. This enzyme takes part in cell dividing via cytosceleton modification. Recently high attention is paid to catabolic enzyme caspase, produced by ced-3 gene. Caspase use the majority of cell structural proteins as substrate. Caspase action plays important role in signal cascade activating endonuclease. The last event induces direct DNA fragmentation [12,17,24]. Deprivation to growth factors (IL-2, hormones), which are necessary for cell dividing, causes apoptosis. Antitumor agents breake the cell cycle in G2/M-phase and lead to apoptosis [10]. In cell cultures apoptosis appears after transition from logarithmic growth phase to stable one when appropriate quantity of cells is achieved. Subcultivation prevents apoptosis is this conditions. Apoptotic process lasts about 90 minutes in cell culture while in vivo it takes about 12-24 hours [21]. The most interesting studies present facts of direct transit of apoptotic cells to M-phase proved by aberrant miltipole spindle existed in these cells [25]. Moreover, mitotic spindle is necessary for apoptosis completion. It was shown by nocadosole (destroying spindle agent) action causing reduction in apoptotic activity more then in 60% of stimulated cells [13]. Entering the M-phase by cells with disorganized karyolemma can explain how caspase permeates nucleus before DNA fragmentation. Signal reception and transduction during preparing to apoptosis and in apoptosis as well are partly similar to those activating cell mitosis. It can be presented schematically like triple phase process: I- initiation, II - activation, III - degradation (Pic.2). So, the most important and interesting are the data, which are proving directly, or indirectly that apoptosis is morphological incarnation of active cell death. Based on facts mentioned above and on regeneration theory [22], it is possible to propose some common mechanism or scenario of apoptosis and it’s relation to mitosis and necrosis. The principle of active cell death means that before entering the apoptosis cell has to complete its certain function or job. If this function is not completed, cell cannot die via apoptosis. By other words, apoptotic cell as well as mitotic cell has to accumulate energy. If mitosis is abrupted by some reasons, energy can be realized in apoptosis. Dying by necrosis, cell has no necessity to accumulate energy. It is evident, because destroying vector is directed inside cell. Cell death via apoptosis as well as cell dividing are the same result of changes in intracellular homeostasis (plastic or energetic) and power vector realizing these processes is directed outside cell. It results from intracellular reparation performed in normal conditions as well as during excessive functional load when it combines with hyperplasic of intracellular structures (with synthesis to destroy ratio >1,). At the same time cells in dividing populations have alternative ways: to divide or to die by apoptosis. If demand to excessive function persists, cell divides and intracellular homeostasis returns to normal values. One of dividing cells differentiates, the other one - can divide again. When functional tension resumes, the number of cells becomes comparatively excessive then necessary for compensation. Initiated to mitosis cells block dividing process, or some special conditions are forming in microenvironment. It leads to activation of certain genes expressing destroying DNA enzymes and initiation of apoptosis. And, at last, when functional tension is extremely intensive for compensation by intracellular hyperplasia, cell is committed to necrosis. It begins from decreasing of intracellular regeneration with damage of cell organelles and membranes and leads to nuclei destroying (synthesis to destroying ratio<1). So, by some sort of “threadbare”, the cells end their physiological life in zones with negative regenerative balance (keratynocytes of epidermis, centrolobular hepatocytes, etc). Typical example of a necrosis in pathological conditions is the infarct with inactive, uncontrolled and nonprogrammer cell death. This apoptotic scenario is adequate for dividing cell populations. In stable or non-renovated cell populations, such as myocardial cells or ganglious CNS cells the mutual apoptotic mechanism and its morphological signs should have their special features, which have to be understood in future. C O N C L U S I O N: According to facts mentioned above, we can conclude, that apoptosis - is programmed, controllable and active cell death, serving as mechanism of compensation and adaptation. It alternates mitosis during decreasing of functional demands. This process is characterized by special morphological picture, with regular internucleosomic DNA fragmentation preceded by structural hyperplasia and causes cell destruction on particles surrounded by membrane fragments. As the rule, in vivo apoptosis is observed together with mitosis by time of action – linked to DNA synthesis- and by place of action – in regenerative zones. The similarity of signal reception and transduction during mitosis and apoptosis initiation and presence of mitotic spindle in apoptotic cells (the sign of M-phase) allow us to conclude that biologically apoptosis is aborted mitosis of excessive cells produced during regeneration. If it is correct, cell mitosis and apoptosis are equally important and related processes of regeneration of renovating cell populations. They provide organism formation in early and late ontogenesis and sustain adequate functional adaptation of organs and systems to changing environmental conditions. “The play of antagonists” so names this principle of functional management by controversial actions in live systems [22]. In spite of controversy of cell death role in regenerative process apoptosis has to be discussed in pathology textbooks not together with necrosis but together with processes of compensation and adaptation. The science is on the very beginning of understanding of tiny apoptotic mechanisms yet. However, the strategy of this fundamental event becomes clear when evaluated in frames of regenerative processes. If regeneration is stated to be forming process, apoptosis can be compared with stiletto of Sculptor, creating these forms according to projects of genome. ABSTRACT: The same mechanism lays in the basis of cell renovation and death – the intracellular regeneration that rules three different cellular states by changing of its activity. They are: mitosis, apoptosis and necrosis. In case of positive intracellular regenerative balance (structure synthesis to destroying ratio >1) changing of intracellular homeostasis appears, which can lead to alternative states – mitosis or apoptosis. We sign out the general similarities of mitosis and apoptosis: 1. The same localization in vivo in regenerative zones. 2. The same time of occurrence linked to period of DNA synthesis. 3. The similarity of stages of signal reception and transduction and morphological signs of M-phase (mitotic spindle) in apoptotic cells. We conclude that biological sense of apoptosis is abortive mitosis of excessive cells produced by regeneration. So, regeneration in dividing cell populations consists of two obligate parts – mitosis and apoptosis. They provide organism formation in early and late ontogenesis and realize adequate adaptation of all systems to changing environmental conditions. Necrosis occurs when negative balance of intracellular regeneration exists (structure synthesis to destroying ratio <1). This type of cell death as some sort of “threadbare” is normal for cells in zones with low regenerative capacity (keratynocytes, hepatocytes, enterocytes etc.). We suggest original schema of mitosis, apoptosis and necrosis relations. REFERENCES 1. 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Exp Cell Res 2000 Aug 1;258(2):261-9 ___________________________________________________________________________________________________________ _______________________________________________________________________________________________________________ P.S. The above-stated materials are completely published in the Collection of scientifically-practical works « 20 years to Clinical hospital № 1 State Unitary Enterprises “ Medical control centre” of affairs of Mayor and the Government of Moscow » (Medpraktika-M, Moscow 2008, 275 p., the scientific editor academician of Russian Academy of Medical Science A.I.Martynov) under the name « Apoptosis and regeneration », p. 236-243. http://apoptosis1.narod.ru/text.doc http://apoptosis1.narod.ru/text.doc Work address: Russian Federation Moscow Poselok “OTRADNOE” Piatnitckoe shosse, 6 km Clinical hospital № 1 State Unitary Enterprises “ Medical centre” Otdelenie Patologicheskoi Anatomii Dr Berezhkov N.V. |
