GAS41 amplification results in overexpression of a new spindle pole protein

Abstract

Amplification is a hallmark of many human tumors but the role of most amplified genes in human tumor development is not yet understood. Previously, we identified a frequently amplified gene in glioma termed glioma-amplified sequence 41 (GAS41). Using the TCGA data portal and performing experiments on HeLa and TX3868, we analyzed the role of GAS41 amplification on GAS41 overexpression and the effect on the cell cycle. Here we show that GAS41 amplification is associated with overexpression in the majority of cases. Both induced and endogenous overexpression of GAS41 leads to an increase in multipolar spindles. We showed that GAS41 is specifically associated with pericentrosome material. As result of an increased GAS41 expression we found bipolar spindles with misaligned chromosomes. This number was even increased by a combined overexpression of GAS41 and a reduced expression of NuMA. We propose that GAS41 amplification may have an effect on the highly altered karyotype of glioblastoma via its role during spindle pole formation.

YEATS4 Is a Novel Oncogene Amplified in Non–Small Cell Lung Cancer That Regulates the p53 Pathway

“…These include MYC, MYCN, TACC1, TACC2, NuMa, AF10, PFDN1 and KIAA1009 (42-46). Analysis of expression data before and after YEATS4 knockdown showed no effect on expression of any binding partners, suggesting that YEATS4 does not control the expression of its binding partners at the mRNA level.…”

“…Analysis of expression data before and after YEATS4 knockdown showed no effect on expression of any binding partners, suggesting that YEATS4 does not control the expression of its binding partners at the mRNA level. To date, the majority of work surrounding YEATS4 has focused primarily on the identification of YEATS4 binding partners with only a few studies having explored the phenotypic effects of YEATS4 amplification, none of which have been performed in lung (34, 46). …”

YEATS4 (YEATS domain containing 4)

“…This interaction was confirmed independently by coimmunoprecipitation, Dot Overlay Assays, Surface Plasmon Resonance, and by a separate study (Munnia et al, 2001). Later studies showed that interaction between NuMA and YEATS4 was cellcycle regulated with the interaction being low in G1 to S, increasing in S phase and being maximal at G2/M (Schmitt et al, 2012). NuMA is a nuclear matrix protein that relocalizes to and anchors microtubules to the spindle poles (reviewed in Haren et al, 2009).…”

“…NuMA is a nuclear matrix protein that relocalizes to and anchors microtubules to the spindle poles (reviewed in Haren et al, 2009). Manipulation of the expression of YEATS4 and NuMA via expression plasmids and siRNA results in an increased rate of spindle defects leading to multipolar spindles and misaligned chromosomes (Schmitt et al, 2012). Additional interactions of YEATS4 with CEP162 (Munnia et al, 2001), and TACC1 -TACC2 -TACC3 (Lauffart et al, 2002;Lauffart et al, 2003), proteins with known roles in centrosomal dynamics during mitosis (Gergley et al, 2000a,b;Leon et al, 2006), have also been identified.…”

“…(Fischer et al, 1997). In a larger study by Schmitt et al (2012) ;q15), resulting in a fusion between YEATS4 and XRCC6BP1 (X-ray repair crosscomplementation group 6 binding protein 1). XRCC6BP1 (AKA ATP23) is involved in doublestranded DNA break repair (Fischer et al, 2013) and, based on homology via its metalloprotease domain, is suggested to be important in the biosynthesis of mitochondrial ATPase (Zeng et al, 2007).…”