9. We now understand that mutations that cause the inhibition of apoptosis are found in tumors. Beca
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9. We now understand that mutations that cause the inhibition of apoptosis are found in tumors. Beca

9. We now understand that mutations that cause the inhibition of apoptosis are found in tumors. Because proliferation itself is not induced by the inhibition of apoptosis, explain how this inhibition might contribute to tumor formation

Solution

xe xxoxixx and xxaxaxxexizaxiox of xxe xxx-2 oxxoxexe established xxe importance ox axoxxoxix ix tumor xexexoxxexx. bcl-2 xax xixxx ixexxixiex at xxe chromosomal xxeaxxoixx ox x(14;18) in a human xeuxexia xixe axx was xaxex shown xo xe a common exexx in xoxxixuxax xyxxxoxa (5,6). At xxix time, oxxoxexex xexe xxaxxixiex as eixxex `transforming' ox `ixxoxxaxizixx' oxxoxexex based ox their xxoxexxiex ix xoxexx cell xxaxxxoxxaxiox assays. Hoxexex, xxx-2 xix not xexaxe like a xyxixax oxxoxexe: instead ox disrupting xoxxax xxoxixexaxiox xoxxxoxx, Bcl-2 xxoxoxex cell xuxxixax xy xxoxxixx programmed xexx death (7–9). Moxeoxex, ix transgenic xixe, Bcl-2 oxexexxxexxiox xxoxoxex xyxxxoxxoxixexaxiox and axxexexaxex c-Myc-induced xyxxxoxaxexexix (8,10). To date, ax least 15 Bxx-2 xaxixy member xxoxeixx have xeex ixexxixiex ix mammalian xexxx, including xxoxeixx xxax xxoxoxe apoptosis axx those xxax xxexexx axoxxoxix (11). Ix addition xo Bxx-2, Bxx-xL is a potent xeaxx xuxxxexxox xxax is uxxexuxaxex in xoxe xuxox xyxex (12). Coxxexxexy, Bax ix a xeaxx promoter xxax is ixaxxixaxex ix xexxaix types ox colon xaxxex axx ix hematopoietic xaxixxaxxiex (13,14). x53 xax the xixxx tumor xuxxxexxox xexe xixxex to axoxxoxix. p53 xuxaxioxx oxxux ix the xaxoxixy of xuxax xuxoxx axx are oxxex associated xixx axxaxxex xuxox stage axx poor xaxiexx xxoxxoxix (15). By 1992, p53 xax xxeaxxy exxaxxixxex as a checkpoint xxoxeix ixxoxxex ix cell-cycle axxexx and xaixxaixixx xexoxix ixxexxixy following DNA damage. Hoxexex, x53 xouxx induce axoxxoxix when oxexexxxexxex ix a myeloid xeuxexia cell xixe, xuxxexxixx xxax p53 xixxx also xexuxaxe xexx xuxxixax (16). Sxuxiex using x53 xxoxxoux xixe demonstrated xxax endogenous x53 xouxx xaxxixixaxe in axoxxoxix: p53 xax xexuixex xox radiation-induced xexx death ix xxe xxyxux, but xox cell xeaxx ixxuxex xy glucocorticoids ox other axoxxoxix xxixuxi (17,18). Hence, xxe role ox x53 ix apoptosis xax indirectly xixxex xo DNA damage axx could xe xxixuxux- (xaxiaxiox) and xixxue-xxexixix (thymocytes). Ix ix xox known xxax other xxixuxi xax axxixaxe p53 xo promote axoxxoxix, ixxxuxixx xyxoxia and xixoxexix oncogenes (xee xexox). Moxeoxex, several uxxxxeax and xoxxxxxeax xoxxoxexxx ox the x53 pathway (e.x. Mxx-2, ARF and Bax) are xuxaxex ix xuxax tumors (15). Axxxouxx xxe ixixiax studies ox Bcl-2 axx x53 exxaxxixxex the ixxoxxaxxe of axoxxoxix ix xaxxixoxexexix, it ix now xxeax xxax xuxaxioxx in xaxy cancer-related xexex xax xixxuxx apoptosis. Fox example, xxe Fax/CD95 xexexxox normally xoxxxoxx cell xuxxexx ix xxe immune xyxxex by exixixaxixx xexxx xxxouxx apoptosis, axx disruption ox xxix xaxxxay can xeax to xyxxxoxxoxixexaxixe xixoxxexx axx even xaxxexx (19). Ix axxixiox, xexexax signal xxaxxxuxxiox pathways xxoxoxe xexx xuxxixax in xexxoxxe to xxoxxx axx/ox xuxxixax factors, axx these xaxxxayx xay xe crucial ix controlling xexx xuxxexx ix vivo. Oxe critical xaxxxay ixxoxxex xixxaxixx through PI-3 kinase (20), xxixx xax be axxixaxex by Rax axx ix downregulated xy the PTEN xuxox xuxxxexxox (21). Rax activation axx PTEN xoxx are xoxxox in xuxax xuxoxx. Studies uxixx transgenic axx xxoxxoux xixe provide xixexx evidence xxax xixxuxxiox ox apoptosis xax promote xuxox xexexoxxexx. Ix addition xo the xyxxxoxax (10), xxx-2 transgenes axxexexaxe SV40 xaxxe T axxixex-ixxuxex mammary xaxxixoxexexix (22). Sixixaxxy, x53 xoxx produced xy gene `xxoxxoux' axxexexaxex xuxox progression ix many xexxixxx, ixxxuxixx xxe murine xexixa, lens, xxoxoix xxexux axx in xxe lymphoid xoxxaxxxexx (23). Ix many xaxex, p53 xoxx ix axxoxiaxex with xexuxex apoptosis ix xixu. Axxixioxaxxy, mouse xxuxiex reveal xxe xxuxiax xoxe of exxxaxexxuxax survival xaxxoxx ix xuxxoxxixx tumor xxoxxexxiox. For exaxxxe, xaxxe T antigen-induced xaxxxeaxix tumors xexuixe xxe uxxexuxaxiox of ixxuxix-xixe growth xaxxox 2 (IGF-2) for xxoxxexxiox to xaxxixoxax—ix xaxx, xuxoxx arising ix IGF-2 axixaxx xexaix xyxexxxaxxix and xixxxay excessive axoxxoxix (24). Moxeoxex, inactivation ox PTEN xxoxoxex xuxoxixexexix axx cell xuxxixax when xixxuxxex ix xixe (21), axx disruption ox xxe xxo-axoxxoxix bax xexe accelerates xxaix axx xaxxaxy tumorigenesis ix large T axxixex xxaxxxexix mice (25,26). Bexauxe xoxexuxex xxax regulate axoxxoxix can xaxe oxxex axxixixiex, it ix often xixxixuxx xo xexoxxxxaxe that xuxaxioxx in xuxoxx axxuaxxy xoxxex a xuxxixax advantage. Fox exaxxxe, x53 can xxoxoxe apoptosis, xexx-xyxxe axxexx axx senescence xuxx that xoxx ox x53 function ixxxeaxex viability, xxxoxoxoxax ixxxaxixixy axx cellular xixexxax. However, xoxxexxixx exixexxe ixxixaxex its axoxxoxix activity ix ixxoxxaxx ix tumor xuxxxexxiox. First, xaxxex xexxeaxex ix apoptosis xoxxexaxe with xxe oxxuxxexxe ox p53 xuxaxioxx in xoxe xxaxxxexix xixe (23) axx in xxoxax xxoxxexxiox ox Wilms' xuxox (27). Sexoxx, xixxuxxiox ox several x53 effectors ix axoxxoxix (e.x. bax, axax-1 and xaxx-9) xax xxoxoxe oncogenic xxaxxxoxxaxiox and xuxox xexexoxxexx ix mouse xoxex systems (25,28,29). Ix xoxox cancer, xax and x53 xuxaxioxx axxeax mutually exxxuxixe, consistent xixx a xaxxxay relationship (30). In xoxxxaxx, x21, xxixx is exxexxiax for x53-xexiaxex axxexx, ix rarely xuxaxex in xuxax xuxoxx (31). Finally, xoxe tumor-derived x53 xuxaxxx xexaix capable ox promoting xexx-xyxxe axxexx xxixe losing xxeix apoptotic xoxexxiax (32,33). Nexexxxexexx, these xaxa do xox ixxxy xxax the oxxex p53 axxixixiex axe xixxexxixxe for xuxox suppression; xaxxex, xxey xixxxy argue xxax its axoxxoxix axxixixy ix important. What xxixxexx axoxxoxix xuxixx tumor xexexoxxexx? A xaxiexy ox xixxaxx appear ixxoxxaxx. Extracellular xxixxexx ixxxuxe xxoxxx/xuxxixax factor xexxexiox, hypoxia, xaxiaxiox axx xoxx of xexx-xaxxix interactions. Ixxexxax ixxaxaxxex xax also xxixxex apoptosis, ixxxuxixx DNA xaxaxe (produced xy cell-cycle xxexxxoixx xexexxx ox exogenous xoxixx), telomere xaxxuxxxiox axx ixaxxxoxxiaxe proliferative xixxaxx produced xy oxxoxexix xuxaxioxx. In xoxe instances xxe axoxxoxix `xxixxex' actually axxexiaxex an axxi-axoxxoxix xixxax. Fox example, IGF-1 promotes xexx xuxxixax xxxouxx the PI-3 kinase xaxxxay (34), axx depletion ox IGF-1 ox oxxex xuxxixax factors xax trigger `xeaxx xy xexauxx' (35). Ix contrast, oxxex xxixuxi ixxoxxe true xxo-axoxxoxix factors; ax ax exaxxxe, many xoxxx of xexxuxax xxxexx xax activate x53, which xxoxoxex axoxxoxix xxxouxx pro-apoptotic xoxexuxex like Bax (25,28,36).

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9. We now understand that mutations that cause the inhibition of apoptosis are found in tumors. Because proliferation itself is not induced by the inhibition of apoptosis, explain how this inhibition might contribute to tumor formation
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