Induction of apoptosis by the Bcl-2 homologue Bak

Chittenden, Thomas; Ea, Harrington; O’Connor, Rosemary; Flemington, Cathy; Rj, Lutz; Gi, Evan; Bc, Guild

doi:10.1038/374733a0

Cited by 687 publications

(364 citation statements)

References 22 publications

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“…There is precedent for this type of dual role with other members of the Bcl2 family. For example, the recently identi®ed family member Bak can promote cell death in some cell types, while promoting cell viability in others (Chittenden et al, 1995;Farrow et al, 1995;Kiefer et al, 1995). Furthermore, Bax has been speculated to have a role in promoting cell death when present as a homodimer, while having a role in maintaining cell viability when present as a heterodimer with Bcl2 (Yang and Korsmeyer, 1996).…”

Section: Discussionmentioning

confidence: 99%

Induction of BCL2 family member MCL1 as an early response to DNA damage

et al. 1997

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When ML-1 human myeloid leukemia cells are exposed to DNA damaging agents, they exhibit dramatic changes in the expression of a variety of gene products. This includes an increase in p53 (wild-type), a decrease in BCL2, a p53-dependent increase in the BCL2 family member BAX, and increases in Growth Arrest and DNA Damage-inducible (GADD) genes such as GADD45; these changes occur as early events in a sequence that culminates in DNA damage-induced apoptosis. DNA damaging agents have now been tested for e ects on expression of another BCL2 family member, MCL1, a gene expressed during ML-1 cell di erentiation. Expression of MCL1 was found to increase upon exposure of ML-1 cells to various types of DNA damaging agents, including ionizing radiation, ultraviolet radiation, and alkylating drugs. The increase in MCL1 occurred rapidly and was transient, levels of the MCL1 mRNA being elevated within 4 h and having returned to near baseline within 24 h. An increase in the Mcl1 protein was also seen, with the maximal increase occurring at an intermediate dose of IR (5 Gray) and lesser increases occurring at either lower or higher doses. The increase in expression of MCL1 was further studied using a panel of human cell lines that includes cells containing or not containing alterations in p53 as well as cells sensitive or insensitive to the apoptosis-inducing e ects of DNA damage. The DNA damage-induced increase in MCL1 mRNA did not depend upon p53 as it was seen in cells lacking functional p53. However, the increase did depend upon susceptibility to apoptosis as it was not seen in cells insensitive to apoptosis-induction by DNA damaging agents. These ®ndings demonstrate that cytotoxic DNA damage causes an increase in the expression of MCL1 along with increases in GADD45 and BAX and a decrease in BCL2. Furthermore, while the increase in GADD45 is seen both in cells that undergo growth arrest and in cells that undergo apoptosis in response to DNA damage, alterations in the pro®le of expression of BCL2 family members occur exclusively in cells that undergo the apoptotic response, with some family members increasing through p53-dependent (BAX) and others through p53-independent (MCL1) pathways. Overall, expression MCL1 can increase during the induction of cell death as well as during the induction of di erentiation.

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Section: Discussionmentioning

confidence: 99%

Induction of BCL2 family member MCL1 as an early response to DNA damage

et al. 1997

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“…There are numerous studies suggesting that overexpression of Bcl-2 or Bcl-x L can block apoptosis by effects at the mitochondrion (Shimizu et al, 1996;Susin et al, 1997;Yang et al, 1997), whereas Bax and Bak have been shown to exert pro-apoptotic activity (Chittenden et al, 1995;Narita et al, 1998). We examined the effect of STS on the expression levels of Bcl-2, Bcl-x L, Bak and Bax proteins.…”

Section: Effect Of Staurosporine On Bcl-2 Bcl-x L Bak and Bax Proteimentioning

confidence: 99%

Apoptotic mechanisms in T47D and MCF-7 human breast cancer cells

et al. 2002

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To investigate the mechanisms underlying apoptosis in breast cancer cells, staurosporine was used as an apoptotic stimulus in the human breast cancer cell lines MCF-7 and T47D. Staurosporine induced dose and time dependent increases in DNA fragmentation which was abrogated by z-VAD-fmk. MCF-7 cells did not express caspase-3, suggesting that DNA fragmentation occurred in the absence of caspase-3 and that other caspases may be involved. Staurosporine induced DEVDase activity in T47D cells suggesting the involvement of caspase-3 and/or caspase-7, yet there was no DEVDase activity in MCF-7 cells, probably ruling out the involvement caspase-7. However, staurosporine induced the cleavage of pro-caspase-6 in MCF-7 cells, but not in T47D cells. Caspase dependent PARP cleavage was detected in MCF-7 cells at 3 h, whereas only partial PARP cleavage was detected in T47D cells and then only after 24 h. Moreover, staurosporine led to cytochrome c release at 2 h in MCF-7 cells and 6 h in T47D cells. In addition, a time dependent and caspase-independent reduction of the mitochondrial transmembrane potential was observed; which appeared to occur after the release of cytochrome c. Translocation of Bax from the cytosol to mitochondria was observed in both cell types, and this preceded cytochrome c release in both T47D and MCF-7 cells. Apoptotic events in both cell types differ temporally, involving activation of different caspases and mitochondrial changes.

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“…This implies the existence of other gene family members also involved in the regulation of apoptosis. A number of other cellular proteins including Bax (Oltvai et al, 1993), Bcl-x (Boise et al, 1993), Bak (Chittenden et al, 1995;Kiefer et al, 1995), Mcl-1 (Kozopas et al, 1993) and A1 (Lin et al, 1993) share highly conserved domains (BH-1 and BH-2; Oltvai et al, 1993) with Bcl-2. Bax is capable of forming homodimers and heterodimers with Bcl-2.…”

Section: Melanoma; Fish Analysismentioning

confidence: 99%