Apoptosis and Cell Proliferation
Because the cleavage sites of the p10 and p20 subunits contain critical aspartate residues and hence potential caspase substrate sequences , other, active caspases can clip the prodomain from inactive caspases 5 , 6. Active caspase 8 promotes cleavage of various downstream caspases, including caspases-3, -6, and Caspase-8 can also cleave the Bcl-2 homologue Bid to reveal an active truncated Bid tBid fragment.
The opposite end of FADD contains a death effector domain DED; hatched boxes that allows recruitment of either procaspase-8 or the related protein c-FLIP, which contains a sequence change in the sequence corresponding to the active site of procaspase-8 black bar , rendering it enzymatically inactive. Caspase-8 can cleave the BH3-only protein Bid, and the resulting truncated Bid tBid can inactivate Bcl-2 in the mitochondrial membrane. This allows the escape of cytochrome c , which clusters with Apaf-1 and caspase-9 in the presence of dATP to activate caspase Active caspase-9 can cleave and activate procaspase-3 to its active form, leading to breakdown of several cytoskeletal proteins and degradation of the inhibitor of caspase-activated DNase ICAD.
Death of lymphocytes, or at least of T cells, can be ascribed to one of two general mechanisms. As an inflammatory response subsides, cytokines can become limiting and this withdrawal leads to apoptosis. This process does not involve Fas but, rather, is governed by the Bcl-2 family and requires Bim, a member of the so-called BH3-only subfamily of apoptotic regulators A second route to T cell death, known as activation-induced cell death AICD , is activated by repeated stimulation by the antigen receptor.
This process does not appear to be regulated by traditional Bcl-2 family members 17 , but AICD induction by superantigens is only slightly delayed in the absence of Fas Clearly other factors — perhaps one or more of the BH3-only proteins — support the deletion of these cells. Nonetheless, the importance of Fas in lymphocyte homeostasis is reflected in mice and humans bearing mutations in the Fas gene, where profound lymphadenopathy and an autoimmune diathesis result 20 , Recent findings suggest that cell death following cytokine withdrawal is dependent not on proximal caspases but, rather, on those that are more downstream.
Thus, mice lacking Fas or FADD or overexpressing CrmA which inhibits caspase-8 all inhibit Fas-induced death but do not block death by cytokine deprivation The reverse is true that is, Fas-induced death is unchanged but cytokine withdrawal is impeded in mice transgenic for Bcl-2, in knockout animals lacking Bim, and in double knockouts lacking both Bak and Bax 22 , However, it does not appear that these two receptor types specialize in the manner that was originally supposed, since recent studies show that TNFR2 can confer signals for both death and growth in T cells In the case of Fas signaling, despite the existence of only a single receptor Fas , there are several instances of signals by this classically proapoptotic molecule promoting increased growth of T cells 29 , 30 , fibroblasts 28 , certain tumors 31 , hepatocytes 32 , and increased differentiation of dendritic cells Fas may also induce the physiological and morphological changes in cardiomyocytes seen in cardiac hypertrophy.
Thus, Badorff et al. This process is necessary for cardiac hypertrophy, and the authors found that in a model of cardiac overload, which ordinarily leads to hypertrophy, the hearts of Fas-deficient lpr mice fail to adapt and instead undergo dilatation.
Each of these cases is worth close scrutiny to determine whether alternate interpretations of the findings are possible. Seattle, Washington, USA , showing that antibodies to Fas that were cytolytic toward tumor cells and cycling T cells were powerfully costimulatory for proliferation and cytokine production with CD3 activation of resting T cells While there remained the possibility that this might result from the antibodies blocking ligation by endogenous FasL, many of the costimulatory anti-Fas antibodies used were cytolytic on other cells.
More recently, this concern was resolved by similar findings using soluble FasL in place of antibodies. Kennedy et al. While both studies used purified T cells, it is still possible that this effect might depend on an accessory cell, for example, on a minor contamination with dendritic cells. Recently, researchers in two groups observed not only that both mouse and human dendritic cells resist FasL-induced cell death, but also that, in these cells, FasL actually induces upregulation of surface B7. Later studies have shown that dendritic cells express high levels of the Fas inhibitor FLIP 36 , which may help explain the diversion of signals from cell death and toward a growth signal pathway.
Cell cycle and apoptosis
In related T cell work, immobilized anti-Fas or soluble FasL alone has been reported to promote proliferation of T cells from patients with systemic lupus erythematosus Furthermore, caspase inhibitors partially blocked this augmented growth. The observations are consistent with those of Suzuki and coworkers 38 , who observed that Fas-Fc can attenuate the proliferation of murine T cells. These latter findings might indicate that blocking FasL with Fas-Fc inhibits Fas costimulation, or, as favored by the authors, that Fas-Fc can induce FasL to exert retrograde positive signals. As the cultures in this study appear to have been confluent, it is unclear whether some of this effect might result from the death of some fibroblasts by anti-Fas, which would then make room for the remaining cells to re-enter cell cycling.
Two reports indicate that Fas can induce growth of tumor cells. It is not clear whether Bcl-2 levels contribute to this unusual feature, since Bcl-2 does not activate cell proliferation, and it generally does not block Fas-induced death in lymphocytes. A second study examined a variety of tumors and observed that only 4 of the 11 Fas-positive nonhematopoietic tumors were sensitive to killing by anti-Fas Moreover, anti-Fas enhanced growth of 3 of the 11 tumors, including one epidermoid carcinoma, one melanoma, and one pancreatic carcinoma.
In these studies, resistance to Fas and enhanced proliferation did not correlate with levels of Bcl-2 expression.
MATERIALS AND METHODS
Two further situations, somewhat more complex given their in vivo settings, also raise the possibility of Fas-induced cell growth. Biancone et al. This phenomenon was dose-dependent and required interaction with Fas, as Fas-deficient lpr mice did not respond in this manner. In addition, apoptotic cells were not observed at any time inside the implant or in the surrounding tissue. In another study, examining liver regeneration in mice after partial hepatectomy 32 , whereas anti-Fas in vivo induced rapid hepatocyte apoptosis as observed earlier 42 , the same Fas antibody increased cell cycling of hepatocytes during liver regeneration.
This change in the response to anti-Fas between resting and regenerating hepatocytes is reminiscent of the differential effects of TNFR1, which also signals cell death in resting hepatocytes 43 but stimulates proliferation during liver regeneration However, increased PCNA expression corresponding to hyperproliferative states was observed in the prickle cell layer in cholesteatoma tissue specimens.
Tsuruhara et al 14 also found an increase in PCNA-positive cells in the prickle cell layer in cholesteatoma tissue specimens. Comparing the immunohistochemical pattern of PCNA expression of normal external ear canal skin with that of cholesteatoma tissues, we demonstrated that in cholesteatoma the suprabasal and upper layer cells, as well as the basal cells, have the ability to undergo cell division. In the samples of normal external ear canal skin, the process of differentiation begins after the cells are detached from the basal layer. We postulate that in cholesteatoma there could be some abnormality in the differentiation process, resulting in the proliferation of detached cells.
However, the proliferation in cholesteatoma epidermal cells is not uncontrolled, as it is in malignant tumors. Our results demonstrate that despite the hyperproliferation in the cholesteatoma epidermis, cells retain the capability to undergo apoptotic cell death. However, in malignant tumors, cells not only divide uncontrollably but they also become resistant to apoptotic cell death. Even though the rate of apoptotic cell death in cholesteatoma is the same as that in normal external ear canal skin, there is a significant increase in the number of dead cells in cholesteatoma owing to hyperproliferation in the epidermal cell layers.
Besides the accumulation of keratinous debris due to a blockage in horizontal keratin transport, increased cell death will also contribute to increased keratinous debris. Recent studies have shown that the expression of wild-type p53 protein is increased in keratinocytes in the prickle cell layer of cholesteatoma epidermis. However, more work is required to clarify the role of apoptotic cell death in cholesteatoma.
All Rights Reserved. Figure 1. View Large Download. Ann Rev Cell Biol. Br J Cancer. Int Rev Cytol. J Biol Chem. J Histochem Cytochem. Acta Otolaryngol Stockh. Otolaryngol Head Neck Surg.
Proliferation, cell cycle and apoptosis in cancer | Nature
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Proliferation, cell cycle and apoptosis in cancer
Original Article. Patients and methods. In situ labeling of apoptotic cells.
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Links between apoptosis, proliferation and the cell cycle.
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