title: Levels of pro-apoptotic regulator Bad and anti-apoptotic regulator Bcl-xL determine the type of the apoptotic logic gate.
abstract: BACKGROUND
  Apoptosis is a tightly regulated process: cellular survive-or-die decisions cannot be accidental and must be unambiguous. Since the suicide program may be initiated in response to numerous stress stimuli, signals transmitted through a number of checkpoints have to be eventually integrated.
  
  
  RESULTS
  In order to analyze possible mechanisms of the integration of multiple pro-apoptotic signals, we constructed a simple model of the Bcl-2 family regulatory module. The module collects upstream signals and processes them into life-or-death decisions by employing interactions between proteins from three subgroups of the Bcl-2 family: pro-apoptotic multidomain effectors, pro-survival multidomain restrainers, and pro-apoptotic single domain BH3-only proteins. Although the model is based on ordinary differential equations (ODEs), it demonstrates that the Bcl-2 family module behaves akin to a Boolean logic gate of the type dependent on levels of BH3-only proteins (represented by Bad) and restrainers (represented by Bcl-xL). A low level of pro-apoptotic Bad or a high level of pro-survival Bcl-xL implies gate AND, which allows for the initiation of apoptosis only when two stress stimuli are simultaneously present: the rise of the p53 killer level and dephosphorylation of kinase Akt. In turn, a high level of Bad or a low level of Bcl-xL implies gate OR, for which any of these stimuli suffices for apoptosis.
  
  
  CONCLUSIONS
  Our study sheds light on possible signal integration mechanisms in cells, and spans a bridge between modeling approaches based on ODEs and on Boolean logic. In the proposed scheme, logic gates switching results from the change of relative abundances of interacting proteins in response to signals and involves system bistability. Consequently, the regulatory system may process two analogous inputs into a digital survive-or-die decision.
authors.affiliation: Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw 02-106, Poland.
authors.forename: Marta N
authors.initials: MN
authors.lastname: Bogdał
authors.forename: Beata
authors.initials: B
authors.lastname: Hat
authors.forename: Marek
authors.initials: M
authors.lastname: Kochańczyk
authors.forename: Tomasz
authors.initials: T
authors.lastname: Lipniacki
mesh_terms: D017209:Apoptosis; D039301:Computers, Molecular; D008128:Logic; D008954:Models, Biological; D015398:Signal Transduction; D051025:bcl-Associated Death Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: D051025:bcl-Associated Death Protein; D051020:bcl-X Protein