TPX2 prompts mitotic survival via the induction of BCL2L1 through YAP1 protein stabilization in human embryonic stem cells
Genetic alterations have been reported for decades in most human embryonic stem cells (hESCs). Survival advantage, a typical trait acquired during long-term in vitro culture, results from the induction of BCL2L1 upon frequent copy number variation (CNV) at locus 20q11.21 and is one of the strongest...
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Published in | Experimental & molecular medicine Vol. 55; no. 1; pp. 32 - 42 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
01.01.2023
Springer Nature B.V 생화학분자생물학회 |
Subjects | |
Online Access | Get full text |
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Summary: | Genetic alterations have been reported for decades in most human embryonic stem cells (hESCs). Survival advantage, a typical trait acquired during long-term in vitro culture, results from the induction of
BCL2L1
upon frequent copy number variation (CNV) at locus 20q11.21 and is one of the strongest candidates associated with genetic alterations that occur via escape from mitotic stress. However, the underlying mechanisms for
BCL2L1
induction remain unknown. Furthermore, abnormal mitosis and the survival advantage that frequently occur in late passage are associated with the expression of
BCL2L1
, which is in locus 20q11.21. In this study, we demonstrated that the expression of
TPX2
, a gene located in 20q11.21, led to
BCL2L1
induction and consequent survival traits under mitotic stress in isogenic pairs of hESCs and human induced pluripotent stem cells (iPSCs) with normal and 20q11.21 CNVs. High Aurora A kinase activity by TPX2 stabilized the YAP1 protein to induce YAP1-dependent
BCL2L1
expression. A chemical inhibitor of Aurora A kinase and knockdown of YAP/TAZ significantly abrogated the high tolerance to mitotic stress through
BCL2L1
suppression. These results suggest that the collective expression of
TPX2
and
BCL2L1
from CNV at loci 20q11.21 and a consequent increase in YAP1 signaling promote genome instability during long-term in vitro hESC culture.
Stem cells: Maintaining stable cell cultures
New details of the molecular mechanisms behind problematic genetic aberrations that can affect cultured human embryonic stem cells could help efforts to maintain stable cell lines that hold great promise for treating a wide variety of diseases. Researchers in South Korea led by Hyuk-Jin Cha at Seoul National University investigated abnormalities in stem cell control systems leading to a condition known as survival advantage, which can allow abnormal cells to proliferate. They identified a gene (
TPX2
) whose expression activates another gene already known to be involved in triggering the survival advantage process. Their research further revealed that the protein encoded by
TPX2
achieves this effect indirectly, by interacting with another protein known to be able to control the activity of specific genes. Revealing this molecular signaling chain could assist culture of stable stem cells. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2092-6413 1226-3613 2092-6413 |
DOI: | 10.1038/s12276-022-00907-9 |