A moderate reduction of Bcl-xL expression protects against tumorigenesis; however, it also increases susceptibility to tissue injury

The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells

“…Likewise, Bcl-xL mRNA levels were found to be fivefold higher in INS-1E cells as compared to islets corroborating the increased Pax4 expression. Suppression of Pax4, and consequently Bcl-xl, leads to increased apoptosis, a phenomenon observed with other pax genes (Bernasconi et al, 1996;Margue et al, 2000;Ostrom et al, 2000;Henderson et al, 2005). Taken together, these findings strongly suggest that increased expression of Pax4 and the activation of its downstream target gene bcl-xl are critical determinants in sustaining the insulinoma phenotype.…”

“…Accordingly, both Pax4 and Bcl-xL mRNA levels were dose-dependently inhibited by increasing amounts of viPax4PD and viPax4HD, resulting in a graded increase of apoptosis. Interestingly, Henderson et al (2005) showed that the moderate reduction in Bcl-xL expression observed in bcl-xl þ /À transgenic mice conferred protection against tumorigenesis. Conversely, high expression levels of Bcl-xL were detected in rhabdomyosarcoma cell lines and conveyed resistance to cell death (Margue et al, 2000).…”

Control of Cellular Bcl-xL Levels by Deamidation-Regulated Degradation

“…Additionally, we have shown that even modest changes in Bcl-x L levels can alter the extent of tissue damage in response to certain types of injury [17]. The finding that mutation of the PEST sequence or treatment with calpain inhibitor I in otherwise untreated cells results in a relative increase of the level of deamidated Bcl-x L demonstrates that Bcl-x L levels are continuously modulated by deamidation, even in normally growing cells.…”

“…For example, increased Bcl-x L expression portends a worse prognosis in pancreatic cancer [4], thyroid cancer [5], follicular lymphoma [6], ovarian cancer [7],[8], hepatocellular carcinoma [9], and prostate cancer [10] and it has been specifically shown that increased levels of Bcl-x L correlate with treatment failure in thyroid cancer [5], ovarian cancer [8], and oropharyngeal cancer [11]. In support of a functional role for Bcl-x L in determining the prognosis and treatment response of patients with these cancers are the findings that (i) there is a “striking” correlation between resistance to treatment with a panel of 122 chemotherapeutic agents and Bcl-x L expression levels when assessed in 60 different types of tumor cells [12]; (ii) overexpression of Bcl-x L confers a multidrug resistance phenotype to tumor cells [13]; (iii) a small molecule or antisense that selectively inhibits Bcl-x L increases sensitivity to chemotherapy in vivo [14],[15]; (iv) at least in some cells, there is a bcl-x gene-dosage effect for resistance to DNA-damaging agents [16]; and (v) increased Bcl-x L expression increases susceptibility to carcinogen-induced tumor formation in mice [17]. When considered together, these findings suggest that tumor cell Bcl-x L levels have an important functional role in determining patient outcome.…”

“…For example, liver cells with decreased Bcl-x L levels demonstrate increased susceptibility to injury [17],[18]; conversely, transgenic overexpression of Bcl-x L protects against liver injury [19]. In this context, it is intriguing that hepatic Bcl-x L expression is upregulated in response to liver injury [20],[21].…”