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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

Solution

xx xxxxxxx and xxxxxxxxxxzxxxxx of xxx xxx-x xxxxxxxx established xxx importance xx xxxxxxxxx xx tumor xxxxxxxxxxx. bcl-2 xxx xxxxx xxxxxxxxxx at xxx chromosomal xxxxxxxxxx xx x(xx;xx) in x human xxxxxxxx xxxx xxx was xxxxx shown xx xx x common xxxxx in xxxxxxxxxx xyxxxxxx (x,x). At xxxx time, xxxxxxxxx xxxx xxxxxxxxxx as xxxxxx `transforming' xx `xxxxxxxxxzxxx' xxxxxxxxx based xx their xxxxxxxxxx xx xxxxxx cell xxxxxxxxxxxxxx assays. xxxxxxx, xxx-x xxx not xxxxxx like x xyxxxxx xxxxxxxx: instead xx disrupting xxxxxx xxxxxxxxxxxxx xxxxxxxx, Bcl-2 xxxxxxxx cell xxxxxxxx xy xxxxxxxx programmed xxxx death (x–x). xxxxxxxx, xx transgenic xxxx, Bcl-2 xxxxxxxxxxxxxx xxxxxxxx xyxxxxxxxxxxxxxxxxx and xxxxxxxxxxx c-Myc-induced xyxxxxxxxxxxxxx (x,xx). xx date, xx least xx xxx-x xxxxxy member xxxxxxxx have xxxx xxxxxxxxxx xx mammalian xxxxx, including xxxxxxxx xxxx xxxxxxx apoptosis xxx those xxxx xxxxxxx xxxxxxxxx (11). xx addition xx xxx-x, xxx-xx is x potent xxxxx xxxxxxxxxx xxxx is xxxxxxxxxxx in xxxx xxxxx xyxxx (12). xxxxxxxxxy, Bax xx x xxxxx promoter xxxx is xxxxxxxxxxx xx xxxxxxx types xx colon xxxxxx xxx xx hematopoietic xxxxxxxxxxxx (13,14). xxx xxx the xxxxx tumor xxxxxxxxxx xxxx xxxxxx to xxxxxxxxx. p53 xxxxxxxxx xxxxx xx the xxxxxxxy of xxxxx xxxxxx xxx are xxxxx associated xxxx xxxxxxxx xxxxx stage xxx poor xxxxxxx xxxxxxxxx (xx). By xxxx, p53 xxx xxxxxxy xxxxxxxxxxx as x checkpoint xxxxxxx xxxxxxxx xx cell-cycle xxxxxx and xxxxxxxxxxx xxxxxxx xxxxxxxxy following xxx damage. xxxxxxx, xxx xxxxx induce xxxxxxxxx when xxxxxxxxxxxxx xx x myeloid xxxxxxxx cell xxxx, xxxxxxxxxx xxxx p53 xxxxx also xxxxxxxx xxxx xxxxxxxx (16). xxxxxxx using xxx xxxxxxxx xxxx demonstrated xxxx endogenous xxx xxxxx xxxxxxxxxxx in xxxxxxxxx: p53 xxx xxxxxxxx xxx radiation-induced xxxx death xx xxx xxyxxx, but xxx cell xxxxx xxxxxxx xy glucocorticoids xx other xxxxxxxxx xxxxxxx (xx,xx). Hence, xxx role xx xxx xx apoptosis xxx indirectly xxxxxx xx xxx damage xxx could xx xxxxxxxx- (xxxxxxxxx) and xxxxxx-xxxxxxxx (thymocytes). xx xx xxx known xxxx other xxxxxxx xxx xxxxxxxx p53 xx promote xxxxxxxxx, xxxxxxxxx xyxxxxx and xxxxxxxxx oncogenes (xxx xxxxx). xxxxxxxx, several xxxxxxxx and xxxxxxxxxx xxxxxxxxxx xx the xxx pathway (x.x. xxx-x, xxx and xxx) are xxxxxxx xx xxxxx tumors (xx). xxxxxxxx xxx xxxxxxx studies xx Bcl-2 xxx xxx xxxxxxxxxxx the xxxxxxxxxx of xxxxxxxxx xx xxxxxxxxxxxxxx, it xx now xxxxx xxxx xxxxxxxxx in xxxy cancer-related xxxxx xxx xxxxxxx apoptosis. xxx example, xxx xxx/xxxx xxxxxxxx normally xxxxxxxx cell xxxxxxx xx xxx immune xyxxxx by xxxxxxxxxxx xxxxx xxxxxxx apoptosis, xxx disruption xx xxxx xxxxxxy can xxxx to xyxxxxxxxxxxxxxxxxx xxxxxxxxx xxx even xxxxxxx (19). xx xxxxxxxx, xxxxxxx signal xxxxxxxxxxxx pathways xxxxxxx xxxx xxxxxxxx in xxxxxxxx to xxxxxx xxx/xx xxxxxxxx factors, xxx these xxxxxxyx xxy xx crucial xx controlling xxxx xxxxxxx xx vivo. xxx critical xxxxxxy xxxxxxxx xxxxxxxxx through xx-x kinase (xx), xxxxx xxx be xxxxxxxxx by xxx xxx xx downregulated xy the xxxx xxxxx xxxxxxxxxx (21). xxx activation xxx xxxx xxxx are xxxxxx in xxxxx xxxxxx. Studies xxxxx transgenic xxx xxxxxxxx xxxx provide xxxxxx evidence xxxx xxxxxxxxxx xx apoptosis xxx promote xxxxx xxxxxxxxxxx. xx addition xx the xyxxxxxxx (xx), xxx-x transgenes xxxxxxxxxx SV40 xxxxx x xxxxxxx-xxxxxxx mammary xxxxxxxxxxxxxx (22). xxxxxxxxy, xxx xxxx produced xy gene `xxxxxxxx' xxxxxxxxxxx xxxxx progression xx many xxxxxxxx, xxxxxxxxx xxx murine xxxxxx, lens, xxxxxxx xxxxxx xxx in xxx lymphoid xxxxxxxxxxx (xx). xx many xxxxx, p53 xxxx xx xxxxxxxxxx with xxxxxxx apoptosis xx xxxx. xxxxxxxxxxxy, mouse xxxxxxx reveal xxx xxxxxxx xxxx of xxxxxxxxxxxxx survival xxxxxxx xx xxxxxxxxxx tumor xxxxxxxxxxx. For xxxxxxx, xxxxx x antigen-induced xxxxxxxxxx tumors xxxxxxx xxx xxxxxxxxxxxx of xxxxxxx-xxxx growth xxxxxx x (xxx-x) for xxxxxxxxxxx to xxxxxxxxxx—xx xxxx, xxxxxx arising xx IGF-2 xxxxxxx xxxxxx xyxxxxxxxxxx and xxxxxxy excessive xxxxxxxxx (xx). xxxxxxxx, inactivation xx PTEN xxxxxxxx xxxxxxxxxxxxx xxx cell xxxxxxxx when xxxxxxxxx xx xxxx (21), xxx disruption xx xxx xxx-xxxxxxxxx bax xxxx accelerates xxxxx xxx xxxxxxy tumorigenesis xx large x xxxxxxx xxxxxxxxxx mice (xx,xx). xxxxxxx xxxxxxxxx xxxx regulate xxxxxxxxx can xxxx xxxxx xxxxxxxxxx, it xx often xxxxxxxxx xx xxxxxxxxxxx that xxxxxxxxx in xxxxxx xxxxxxxy xxxxxx a xxxxxxxx advantage. xxx xxxxxxx, xxx can xxxxxxx apoptosis, xxxx-xyxxx xxxxxx xxx senescence xxxx that xxxx xx xxx function xxxxxxxxx viability, xxxxxxxxxxx xxxxxxxxxxy xxx cellular xxxxxxxx. However, xxxxxxxxxx xxxxxxxx xxxxxxxxx its xxxxxxxxx activity xx xxxxxxxxx xx tumor xxxxxxxxxxx. First, xxxxxx xxxxxxxxx xx apoptosis xxxxxxxxx with xxx xxxxxxxxxx xx p53 xxxxxxxxx in xxxx xxxxxxxxxx xxxx (23) xxx in xxxxxx xxxxxxxxxxx xx Wilms' xxxxx (27). xxxxxx, xxxxxxxxxx xx several xxx effectors xx xxxxxxxxx (x.x. bax, xxxx-x and xxxx-x) xxx xxxxxxx oncogenic xxxxxxxxxxxxxx and xxxxx xxxxxxxxxxx xx mouse xxxxx systems (xx,xx,xx). xx xxxxx cancer, xxx and xxx xxxxxxxxx xxxxxx mutually xxxxxxxxx, consistent xxxx x xxxxxxy relationship (xx). In xxxxxxxx, xxx, xxxxx is xxxxxxxxx for xxx-xxxxxxxx xxxxxx, xx rarely xxxxxxx in xxxxx xxxxxx (xx). Finally, xxxx tumor-derived xxx xxxxxxx xxxxxx capable xx promoting xxxx-xyxxx xxxxxx xxxxx losing xxxxx apoptotic xxxxxxxxx (xx,xx). xxxxxxxxxxxx, these xxxx do xxx xxxxy xxxx the xxxxx p53 xxxxxxxxxx xxx xxxxxxxxxxx for xxxxx suppression; xxxxxx, xxxy xxxxxy argue xxxx its xxxxxxxxx xxxxxxxy xx important. What xxxxxxxx xxxxxxxxx xxxxxx tumor xxxxxxxxxxx? A xxxxxxy xx xxxxxxx appear xxxxxxxxx. Extracellular xxxxxxxx xxxxxxx xxxxxx/xxxxxxxx factor xxxxxxxxx, hypoxia, xxxxxxxxx xxx xxxx of xxxx-xxxxxx interactions. xxxxxxxx xxxxxxxxxx xxx also xxxxxxx apoptosis, xxxxxxxxx xxx xxxxxx (produced xy cell-cycle xxxxxxxxxx xxxxxxx xx exogenous xxxxxx), telomere xxxxxxxxxxx xxx xxxxxxxxxxxxx proliferative xxxxxxx produced xy xxxxxxxxx xxxxxxxxx. In xxxx instances xxx xxxxxxxxx `xxxxxxx' actually xxxxxxxxxx an xxxx-xxxxxxxxx xxxxxx. xxx example, xxx-x promotes xxxx xxxxxxxx xxxxxxx the xx-x kinase xxxxxxy (xx), xxx depletion xx IGF-1 xx xxxxx xxxxxxxx factors xxx trigger `xxxxx xy xxxxxxx' (35). xx contrast, xxxxx xxxxxxx xxxxxxx true xxx-xxxxxxxxx factors; xx xx xxxxxxx, many xxxxx of xxxxxxxx xxxxxx xxx activate xxx, which xxxxxxxx xxxxxxxxx xxxxxxx pro-apoptotic xxxxxxxxx like xxx (xx,xx,xx).

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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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