Tousled-like kinase mediated a new type of cell death pathway in Drosophila

Abstract

Programmed cell death (PCD) has an important role in sculpting organisms during development. However, much remains to be learned about the molecular mechanism of PCD. We found that ectopic expression of tousled-like kinase (tlk) in Drosophila initiated a new type of cell death. Furthermore, the TLK-induced cell death is likely to be independent of the canonical caspase pathway and other known caspase-independent pathways. Genetically, atg2 RNAi could rescue the TLK-induced cell death, and this function of atg2 was likely distinct from its role in autophagy. In the developing retina, loss of tlk resulted in reduced PCD in the interommatidial cells (IOCs). Similarly, an increased number of IOCs was present in the atg2 deletion mutant clones. However, double knockdown of tlk and atg2 by RNAi did not have a synergistic effect. These results suggested that ATG2 may function downstream of TLK. In addition to a role in development, tlk and atg2 RNAi could rescue calcium overload-induced cell death. Together, our results suggest that TLK mediates a new type of cell death pathway that occurs in both development and calcium cytotoxicity.

Knockdown of Tousled‑like kinase 1 inhibits survival of glioblastoma multiforme cells

“…This is in line with previous data, where TLK1 overexpression in breast and prostate cancer resulted in resistance to radiotherapy (52). By contrast, Zhang et al (53) observed that TLK1 overexpression in Drosophila eyes induced cell death and pigmentation loss, suggesting that TLK1 may serve a different role in eye development.…”

Inactive Tlk associating with Tak1 increases p38 MAPK activity to prolong the G2 phase

“…This differs from the severe rough-eye phenotype caused by Tak1 overexpression alone, in which JNK activity is activated and induces apoptosis 41 . Although Tlk overexpression induces cell death, the regulatory pathway is not through apoptosis 42 . Thus, the difference may result from alternative functions of Tak1 when it works with different partners.…”

Epigenetic Regulation of ALS and CMT: A Lesson from Drosophila Models

“…By this genetic screening, we identified 14 genes whose mutation or knockdown effectively suppressed the rough eye phenotype induced by caz knockdown, whereas there were 5 genes whose mutation or knockdown strongly enhanced the rough eye phenotype (to be published elsewhere). The 14 suppressor genes included Histone acetyltransferase 1 (Hat1) [ 120 , 121 ], chameau ( chm ) [ 122 , 123 ], N(alpha)-acetyltransferase 60 (Naa60) [ 124 ], Negative Cofactor 2β (Nc2β) [ 125 ], Spt7 [ 126 ], TBP-associated factor 1(Taf1) [ 127 ], will die slowly (wds) [ 125 ], Sirtuin 2 (Sirt2) [ 128 ], Methyltransferase 2(Mt2) [ 129 ], extra sexcombs (esc) [ 130 ], grappa (gpp) [ 131 ], SET domain containing 1 (Set1) [ 132 ], Tousled-like kinase (Tlk) [ 133 ], and Vacuolar protein sorting 11(Vps11) [ 134 ]. Among them, mutations of chm and Naa60 suppressed the locomotive defects and morphological defects of synapse at the NMJ induced by caz knockdown (to be published elsewhere).…”