The SIL (STIL) gene in mitosis and cancer

Konference: 2009 5. sympózium a workshop molekulární patologie a histo-cyto-chemie

Kategorie: Maligní lymfomy a leukémie

Téma: Keynote lectures of invited speakers

Číslo abstraktu: 010

Autoři: Dr. Castiel Asher, M.Sc.

The SIL gene (SCL Interrupting Locus) was cloned from the most common chromosomal rearrangement in T cell acute lymphoblastic leukemia (T-ALL). In this rearrangement, SIL promoter assumes control of a downstream gene, SCL. The resulting aberrant expression of SCL leads to the development of leukemia. The SIL gene encodes a large (150kDa) cytosolic protein, with almost no known functional motifs or cellular role. SIL mRNA expression is higher in rapidly proliferating cells and tissues, and decreases rapidly during terminal differentiation. The SIL protein reaches peak levels in mitosis during which it is phosphorylated and then degraded on transition to G1. SIL importance to cell growth and survival is supported by the phenotype of mouse and zebra fish embryos lacking a functional SIL protein. In both species, the loss of SIL is embryonically lethal and is associated with marked apoptosis of the developing nervous system. The phenotype of SIL-/-embryos, together with recent published data, suggests that SIL is required for the Sonic Hedgehog (Shh) pathway, a critical pathway for normal development and tumorgenesis. Mutations in the Shh pathway are associated with developmental defects and neoplasia, and over activation of this pathway can frequently be found in cancer. Additional data published recently show that SIL is mutated in the Primary Microcephaly Syndrome, together with other mutations in centrosomal genes, suggesting that SIL is a centrosomal protein.

We have previously shown that SIL is over expressed in multiple types of cancers and its expression correlates with the expression of mitotic checkpoint genes. To understand the role of SIL in cancer, we have constructed an inducible RNAi system targeting SIL in colon cancer cell line. Knockdown of SIL blocks mitotic entry and causes apoptosis of these colon cancer cells in vitro and in vivo. The SIL knockdown related death phenotype was also observed in a variety of cancer cells representing the most common types of human cancer (cervical, lung, breast, prostate, gliomas and renal cancer) using anti-SIL siRNA oligonucleotides. This lethal phenotype can be rescued by the murine SIL, showing specificity of the siRNA effect. SIL is not necessary, however, for survival of normal proliferating cells as there are mouse embryonic stem cells and fibroblasts that are negative for the SIL gene.

SIL seems to be a novel regulator of mitotic entry, and thus crucial for the survival of cancer cells. Since cancer cells are extremely sensitive to anti-mitotic drugs, much effort is being invested in the development of drugs targeting mitotic regulators. Thus, targeting SIL (by either our shRNA or specific small inhibitors) may be a novel anti-cancer therapy. Since SIL may be a part of a novel mitotic and survival pathway, the combination of anti-SIL therapy with exiting mitotic drugs may improve anti-cancer treatment efficacy.

Datum přednesení příspěvku: 24. 4. 2009