The role of GTSE1 in G2/M progression after G2 checkpoint

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Homo sapiens
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GTSE1 (B99) was identified as a microtubule-associated protein product of the mouse B99 gene, which exhibits both a cell cycle regulated expression, with highest levels in G2, and DNA damage triggered expression under direct control of TP53 (p53) (Utrera et al. 1998, Collavin et al. 2000). Human GTSE1, similar to the mouse counterpart, binds to microtubules, shows cell cycle regulated expression with a peak in G2 and plays a role in G2 checkpoint recovery after DNA damage but is not transcriptionally regulated by TP53 (Monte et al. 2003, Monte et al. 2004, Scolz et al. 2012).

In G1 cells, GTSE1 is found at the microtubule lattice, likely due to direct binding to tubulin. An evolutionarily conserved interaction between GTSE1 and MAPRE1 (EB1), a microtubule plus end protein, promotes GTSE1 localization to the growing tip of the microtubules, which contributes to cell migration and is likely involved in cancer cell invasiveness. Highly invasive breast cancer cell lines exhibit high GTSE1 levels in G1, while GTSE1 levels in G1 are normally low. At the beginning of mitotic prometaphase, GTSE1 is phosphorylated by mitotic kinase(s), possibly CDK1, in proximity to the MAPRE1-binding region, causing GTSE1 dissociation from the plus end microtubule ends (Scolz et al. 2012).

During G2 checkpoint recovery (cell cycle re-entry after DNA damage induced G2 arrest), GTSE1 relocates to the nucleus where it binds TP53 and, in an MDM2-dependent manner, promotes TP53 cytoplasmic translocation and proteasome mediated degradation (Monte et al. 2003, Monte et al. 2004). Relocation of GTSE1 to the nucleus in G2 phase depends on PLK1-mediated phosphorylation of GTSE1 (Liu et al. 2010).

GTSE1-facilitated down-regulation of TP53 in G2 allows cells to avoid TP53 mediated apoptosis upon DNA damage and to re-enter cell cycle (Monte et al. 2003). While TP53 down-regulation mediated by GTSE1 in G2 correlates with decreased expression of TP53 target genes involved in apoptosis and cell cycle arrest, GTSE1 can also increase the half-life of the TP53 target p21 (CDKN1A). GTSE1-mediated stabilization of CDKN1A involves interaction of GTSE1 with CDKN1A and its chaperone complex, consisting of HSP90 and FKBPL (WISp39), and may be involved in resistance to paclitaxel treatment (Bublik et al. 2010).

Literature References
PubMed ID Title Journal Year
20577264 Polo-like kinase 1 phosphorylation of G2 and S-phase-expressed 1 protein is essential for p53 inactivation during G2 checkpoint recovery

Liu, XS, Song, B, Li, H, Liu, X

EMBO Rep. 2010
23236459 GTSE1 is a microtubule plus-end tracking protein that regulates EB1-dependent cell migration

Piazza, S, Hyman, AA, Scolz, M, Schneider, C, Bublik, DR, Peche, LY, Ellenberg, J, Widlund, PO, Hubner, N, Reber, S, Monte, M, Bird, AW, Ciani, Y, Isokane, M

PLoS ONE 2012
20018861 Human GTSE-1 regulates p21(CIP1/WAF1) stability conferring resistance to paclitaxel treatment

Schneider, C, Bublik, DR, Monte, M, Triolo, G, Scolz, M

J. Biol. Chem. 2010
12750368 The cell cycle-regulated protein human GTSE-1 controls DNA damage-induced apoptosis by affecting p53 function

Del Sal, G, Schneider, C, Buscemi, G, Sandy, P, Monte, M, Benetti, R

J. Biol. Chem. 2003
9724637 A novel p53-inducible gene coding for a microtubule-localized protein with G2-phase-specific expression

Delia, D, Collavin, L, Lazarević, D, Schneider, C, Utrera, R

EMBO J. 1998
14707141 hGTSE-1 expression stimulates cytoplasmic localization of p53

Del Sal, G, Collavin, L, Schneider, C, Monte, M, Marchionni, L, Benetti, R

J. Biol. Chem. 2004
10984615 Cell-cycle regulation of the p53-inducible gene B99

Monte, M, Collavin, L, Schneider, C, Pfleger, C, Verardo, R

FEBS Lett. 2000
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