The loss of the BH3-only Bcl-2 family member Bid delays T-cell leukemogenesis in Atm−/− mice

Abstract

Multicellular organisms maintain genomic integrity and resist tumorigenesis through a tightly regulated DNA damage response (DDR) that prevents propagation of deleterious mutations either through DNA repair or programmed cell death. An impaired DDR leads to tumorigenesis that is accelerated when programmed cell death is prevented. Loss of the ATM (ataxia telangiectasia mutated)-mediated DDR in mice results in T-cell leukemia driven by accumulation of DNA damage accrued during normal T-cell development. Pro-apoptotic BH3-only Bid is a substrate of Atm, and Bid phosphorylation is required for proper cell cycle checkpoint control and regulation of hematopoietic function. In this report, we demonstrate that, surprisingly, loss of Bid increases the latency of leukemogenesis in Atm À / À mice. Bid À / À Atm À / À mice display impaired checkpoint control and increased cell death of DN3 thymocytes. Loss of Bid thus inhibits T-cell tumorigenesis by increasing clearance of damaged cells, and preventing propagation of deleterious mutations.

The BH3‐only protein BID impairs the p38‐mediated stress response and promotes hepatocarcinogenesis during chronic liver injury in mice

“…Consequently, proapoptotic molecules are supposed to induce apoptosis and prevent tumor development. Contrary to this expectation, two previous studies with independent mouse models showed that loss of proapoptotic BID delays tumor development . In line with these findings, loss of BID significantly delayed tumor development after Fah ‐mediated and HBsTg ‐driven chronic injury.…”

“…Treatment with the carcinogen DEN significantly delayed tumor development in Bid −/− mice, which was attributed to impaired hepatocyte proliferation . Moreover, loss of BID delayed T‐cell leukemogenesis in Atm − / − mice …”

Bid-ding for mercy: twisted killer in action

“…The arguments regarding the mechanism by which tumor suppression is achieved in the context of ATM-loss, however, are different. 1 The authors and others have previously shown that Bid was involved in the DNA damage response. 16,17 This role of Bid has been disputed and was the subject of controversial debate 18-20 that we will not be able to resolve in this editorial.…”

Context Dependent Role of P53 Up-Regulated Modulator of Apoptosis (Puma) During Liver Degeneration and Regeneration

“…The patho physiologic role of apoptosis is complicated by contradictory evidences where lack of apoptosis or increased apoptosis may both result in carcinogenesis depending on the microenvironment and external influences. Our group and Qiu W, et al [41] uncovered the long term controversy on the ambivalent role of the proapoptotic BH3 only protein Bid in tumorigenesis [16,[40][41][42] and Puma in carcinogen (i.e. DEN) driven liver cancer model of mice [16].…”