Abstract
Endoplasmic reticulum (ER) calcium homeostasis plays an essential role in cellular calcium signaling, intra-ER protein chaperoning and maturation, as well as in the interaction of the ER with other organelles. Calcium is accumulated in the ER by sarco/endoplasmic reticulum calcium ATPases (SERCA enzymes) that generate by active, ATP-dependent transport, a several thousand-fold calcium ion concentration gradient between the cytosol (low nanomolar) and the ER lumen (high micromolar). SERCA enzymes are coded by three genes that by alternative splicing give rise to several isoforms, which can display isoform-specific calcium transport characteristics. SERCA expression levels and isoenzyme composition vary according to cell type, and this constitutes a mechanism whereby ER calcium homeostasis is adapted to the signaling and metabolic needs of the cell, depending on its phenotype, its state of activation and differentiation. As reviewed here, in several normal epithelial cell types including bronchial, mammary, gastric, colonic and choroid plexus epithelium, as well as in mature cells of hematopoietic origin such as pumps are simultaneously expressed, whereas in corresponding tumors and leukemias SERCA3 expression is selectively down-regulated. SERCA3 expression is restored during the pharmacologically induced differentiation of various cancer and leukemia cell types. SERCA3 is a useful marker for the study of cell differentiation, and the loss of SERCA3 expression constitutes a previously unrecognized example of the remodeling of calcium homeostasis in tumors.
Highlights
These observations when taken together indicate that the induction of SERCA3 expression is part of the differentiation program of acute promyelocytic leukemia cells, that a functional crosstalk exists between Endoplasmic reticulum (ER)-dependent calcium sequestration and the control of acute promyelocytic leukemia cell differentiation, and illustrate the possibility of drug repurposing as SERCA inhibitors
Considering that the SERCA2b isoform will be nearly fully activated by calcium already at resting cytosolic calcium levels and unable to compensate for this calcium leakage, a new dynamic equilibrium will be established with higher cytosolic and lower intra-ER calcium concentrations, even when SERCA2b expression is maintained, rather than decreased in parallel with the induction of SERCA3 expression
Observations made on multiple different tissue and cell types and their tumors of various degrees of malignancy show that whereas several normal epithelial cell types, as well as cells of hematopoietic origin express simultaneously SERCA2b and SERCA3-type calcium pumps, SERCA3 expression is decreased or lost in corresponding tumors or leukemias
Summary
Calcium signaling is based on changes of cytosolic and intra-organellar free calcium ion concentrations. Because the regulation by cytosolic calcium levels of the transport activity of these proteins can differ, their simultaneous action during a calcium-dependent cell activation event can generate highly dynamic situations in terms of calcium transport, where the relative contribution of individual transport proteins may change depending on the evolution of the cytosolic calcium concentration This can lead to crosstalk, partial redundancy and compensatory phenomena among calcium transporters. Tmhoedmuloadtiuolnatoiofncoalfcciaulmciusmignsiaglns ablsybSyESRECRAC-Ade-dpeepnednednetnctaclacilucimumsesqeuquesetsrtartaitoinonccoonnsstittiututetessaa uunniiqquuee mmeecchhaanniissmm ffoorr tthhee ccoonnttrrooll ooff ccaallcciiuumm--ddeeppeennddeenntt cceellll aaccttiivvaattiioonn. CCyyttoossoolliicc ccaallcciiuumm ccaann aallssoo bbee ttaakkeenn uupp bbyy mmiittoocchhoonnddrriiaa tthhrroouugghh tthhee MMCCUU aanndd iiss eelliimmiinnaatteedd ffrroomm tthhee cceellll tthhrroouugghh PPMMCCAA--ttyyppee ccaallcciiuumm ppuummppss aanndd ssooddiiuumm//ccaallcciiuummeexxcchhaannggeersrs(N(NCCXX) )initnotothteheexetxratrcaeclleullluarlamr emdeiudmiumthatthcaotnctoanintasicnaslcciaulmciuimonsioinnsthine tlohwe lmowillimmiollliamr oralanrgrea. CCyyttoossoolliicc ccaallcciiuumm ccaann aallssoo bbee ttaakkeenn uupp bbyy mmiittoocchhoonnddrriiaa tthhrroouugghh tthhee MMCCUU aanndd iiss eelliimmiinnaatteedd ffrroomm tthhee cceellll tthhrroouugghh PPMMCCAA--ttyyppee ccaallcciiuumm ppuummppss aanndd ssooddiiuumm//ccaallcciiuummeexxcchhaannggeersrs(N(NCCXX) )initnotothteheexetxratrcaeclleullluarlamr emdeiudmiumthatthcaotnctoanintasicnaslcciaulmciuimonsioinnsthine tlohwe lmowillimmiollliamr oralanrgrea. nTghee. cTohnececrotnedceartcetidonacotfiotnheosef tmheecsehamniescmhasnleisamdss tloeathdes etostathbleisehsmtaebnlitsohfmreesnttinogf rceysttoinsogliccyctaolscoiulimc cleavlceilusm(lolwevnelasno(lmowolanra).noCmalocliaurm). sCeaqlucieusmteresdeqiunetshteereEdR i(nin tthhee hEiRgh(imn icthroemhoilgahr mcoinccroenmtoralatironcoranncegnet)rcaatnioinnterarancgtew) icthanSTiInMterparcottewinisth, leSaTdIiMng tporionteaicntisv, atleioandionfgcatpoaciintaatcitviveactaiolcniumof cinaflpuacxi,taastivweecllaalcsiuwmithincfalulcxiu, ams-wbienldl iansgwEiRthcchaalpcieurmon-besinsduicnhgaEsRcaclhreatpiceurolinne.s such as calreticulin
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