Chapter 4: Regulation of Clusterin activity by calcium.
In this chapter, the attention is put on Ca(2+) effect on Clusterin (CLU) activity. We showed that two CLU forms (secreted and nuclear) are differently regulated by Ca(2+) and that Ca(2+) fluxes affect CLU gene expression. A secretory form (sCLU) protects cell viability whereas nuclear form (nCLU) is proapoptotic. Based on available data we suggest, that different CLU forms play opposite roles, depending on intracellular Ca(2+) concentration, time-course of Ca(2+) current, intracellular Ca(2+) compartmentalization, and final Ca(2+) targets. Discussion will be motivated on how CLU acts on cell in response to Ca(2+) waves. The impact of Ca(2+) on CLU gene activity and transcription, posttranscriptional modifications, translation of CLU mRNA, and posttranslational changes as well as biological effects of CLU will be discussed. We will also examine how Ca(2+) signal and Ca(2+)-dependent proteins are attributable to changes in CLU characteristics. Some elucidation of CLU gene activity, CLU protein formation, maturation, secretion, and intracellular translocations in response to Ca(2+) is presented. In response to cell stress (i.e., DNA damage) CLU gene is activated. We assume that commonly upregulated mRNA for nCLU versus sCLU and vice versa are dependent on Ca(2+) accessibility and its intracellular distribution. It looks as if at low intracellular Ca(2+) the delay in cell cycle allows more time for DNA repair; otherwise, cells undergo nCLU-dependent apoptosis. If cells are about to survive, intrinsic apoptosis is abrogated by sCLU interacting with activated Bax. In conclusion, a narrow range of intracellular Ca(2+) concentrations is responsible for the decision whether nCLU is mobilized (apoptosis) or sCLU is appointed to improve survival. Since the discovery of CLU, a huge research progress has been done. Nonetheless we feel that much work is left ahead before remaining uncertainties related to Ca(2+) signal and the respective roles of CLU proteins are unraveled.
Pajak
Beata
B
Department of Cell Ultrastructure, Mossakowski Medical Research Center, Polish Academy of Sciences, 02-106 Warsaw, Poland.
Orzechowski
Arkadiusz
A
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D051152:Clusterin / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D021381:Protein Transport / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D051152:Clusterin; D002118:Calcium