INVESTIGADORES
ALVAREZ Sergio Eduardo
congresos y reuniones científicas
Título:
Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a "come and get me' signal
Autor/es:
ALVAREZ SE; GUDE DR; PAUGH SW; MITRA P; YU J; GRIFFITHS R; BARBOUR S; MILSTIEN S; SPIEGEL S
Lugar:
San Luis Argentina
Reunión:
Jornada; II Jornadas de Divulgacion IMIBIO-SL; 2009
Resumen:
Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates myriad important cellular processes including growth, survival, cytoskeleton rearrangements, motility, and immunity. Here we report that treatment of Jurkat and U937 leukemia cells with the pan sphingosine kinase (SphK) inhibitor N,N-dimethylsphingosine to block S1P formation, surprisingly caused a large increase in expression of SphK1 concomitant with induction of apoptosis. Another SphK inhibitor, D,L-threo-dihydrosphingosine, also induced apoptosis and produced dramatic increases in SphK1 expression. However, upregulation of SphK1 was not a specific effect of its inhibition but rather was a consequence of apoptotic stress. The chemotherapeutic drug doxorubicin, a potent inducer of apoptosis in these cells, also stimulated SphK1 expression and activity and promoted S1P secretion. The caspase inhibitor ZVAD not only reduced doxorubicin-induced lethality but also the increased expression of SphK1 and secretion of S1P. Apoptotic cells secrete chemotactic factor(s) to attract phagocytic cells and we found that S1P potently stimulated chemotaxis of monocytic THP-1 and U937 cells and primary monocytes and macrophages. Collectively, out data suggest that apoptotic cells may upregulate SphK1 to produce and secrete S1P that serves as a “come-and-get-me” signal for scavenger cells to engulf them in order to prevent necrosis.