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

Abstract

To guard genome integrity, response mechanisms coordinately execute the G2/M checkpoint in responding to stress. p38 MAPK is activated to prolong the G2 phase for completion of damage repair. Tlk activity is required for DNA repair, chromosome segregation and G2 recovery. However, the involvement of Tlk in G2 recovery differs from previous findings that Tlk overexpression delays the G2/M transition. To clarify this difference, genetic interaction experiments were performed using the second mitotic wave as model system. The results indicate that Tlk overexpression prolongs the G2 phase through p38 MAPK activation, independent of Tlk kinase activity. The results of co-immunoprecipitation, database search and RNAi screening suggest that eEF1α1 and Hsc70-5 links Tlk to Tak1. Reduced gene activities of Tlk, Hsc70-5, eEF1α1 and/or Tak1 couldn’t prolong the G2 phase induced by heat shock, indicating that these proteins work together to elevate p38 MAPK activity. In contrast, a high level of wild type Tlk decreases phosphorylated p38 MAPK levels. Thus, the difference is explained by a dual function of Tlk. When under stress, inactive Tlk increases p38 MAPK activity to prolong the G2 phase, and then activated Tlk modulates activities of p38 MAPK and Asf1 to promote G2 recovery afterwards.

TAK1 inhibition increases proliferation and differentiation of chick retinal cells

“…This finding is indicative of TAK1 inhibiting progression though G1 of the cell cycle, consistent with our observations that the inhibition of TAK1 in the retina leads to an increase in cell cycle progression and an increase in synthesis and G2 to M transition, leading to an increase in both proliferating and differentiating cells. TAK1 has also been implicated in reducing cell cycle progression following DNA damage in cells ( Liaw and Chiang 2019 ). Inactive tousled-like kinase (TLK) bound to TAK1 increased p38 kinase activity, leading to an increased G2 phase.…”

Pan-Cancer Analysis Reveals Prognostic Potential of ANGPTL2 and Its Implications in Tumor Microenvironment

“…We downloaded a standardized pan-cancer dataset(TCGA,TARGET,GTEx)from UCSC(https://xenabrowser.net/).The ENSG00000136859(ANGPTL2)gene expression data from a variety of samples were subjected to a log2 transformation(X + 0.001),after which the transformed expression pro les were mapped to GeneSymbol.Further,we used the R package ESTIMATE(version 1.0.13)which can calculate the immune score,stromal score,and ESTIMATE score for each tumor sample in the TCGA database to calculate ESTIMATE scores for each patient in each tumor based on gene expression. [22] Additionally,We downloaded a standardized pan-cancer dataset(TCGA,TARGET,GTEx)from UCSC(https://xenabrowser.net/).Further,we extracted ENSG00000136859(ANGPTL2)gene and 60 genes of Immune checkpoint pathway(Inhibitory (24)and Stimulatory(36),derived from The Immune Landscape of Cancer.DOI: 10.1016/j.i mmuni.2018.03.023)of marker genes expressed in each sample data,we screened the sample source for further: Primary Solid Tumor,Primary Tumor,Primary Blood Derived Cancer-Bone Marrow,Primary Blood Derived Cancer-Peripheral For Blood samples,we also ltered all normal samples,and further performed log2(x + 0.001)transformations for each expression value.Next,we calculated the pearson correlation between ENSG00000136859(ANGPTL2)and the marker genes of ve immune pathways.…”

The Tousled-like kinases regulate genome and epigenome stability: implications in development and disease

“…The previously described interaction of TLK1 with RAD9, that has multiple roles in the response to DNA damage, has been linked to G2/M checkpoint recovery [30,32,33], although other reports implicated TLK2, but not TLK1, in G2/M checkpoint recovery through ASF1a-mediated transcriptional regulation [67] (Figure 3). Conversely, TLK2 overexpression was also shown to impair the DNA damage-induced G2/M checkpoint in human cancer cells and Tlk overexpression prolonged G2 in D. melanogaster independently of its activity [68,69]. These may explain the observation that overexpression of TLK1B in mouse cells confers enhanced resistance to ionizing radiation, that is more toxic in highly proliferative cells [13].…”