Cells and mice with reduced levels of CENP-E, a mitosis-specific centromere-linked motor protein, develop aneuploidaneuploidy and chromosomal instability both in vitro and in vivo. This demonstrates that decreased CENP-E function is sufficient to drive the generation of abnormal chromosome numbers and associated genomic instability. [@weaver_aneuploidy_2007]
Definitions
- CENP-E
- aneuploidaneuploidy
- chromosomal instability
- mitosis
- centromere
- motor protein
- in vitro
- in vivo
Synthesis
CENP-E reduction, which affects a mitosis-specific motor protein involved in kinetochore-microtubule attachment and chromosome segregation, generates both aneuploidy and chromosomal instability through a mechanism linked to elevated merotely—the improper attachment of microtubules to chromosomes during mitosis. This establishes a mechanistic pathway whereby disruption of CENP-E function increases chromosome missegregation rates during consecutive cell divisions, driving previously stable near-diploid cells into a chromosomally unstable state characterized by ongoing changes in chromosome number. The resulting chromosomal instability promotes immune cell infiltration into tumors, representing a fitness cost that aneuploid cells must overcome through adaptive mechanisms such as Stat1 inactivation combined with Myc activation to evade immune surveillance. However, it remains contested whether chromosome missegregation alone is sufficient for aneuploid cell propagation, as missegregation compromises proliferation in diploid cells, and the precise contribution of CENP-E reduction relative to other non-classic mitotic defects in sustaining chromosomal instability across diverse tumor contexts remains incompletely resolved.
Related
- Stat1 inactivation mechanism is conserved between mouse and human aneuploid cancers
- Mps1 truncation-induced CIN generates convergent recurrent chromosome gains
- Chromosomal instability promotes immune cell infiltration into tumors
- Merotely causes chromosome missegregation in unstable cells
- Multipolar divisions are rare and typically produce inviable progeny
- Aneuploid cancers inactivate Stat1 to circumvent immune surveillance
- Aneuploidy increases spontaneous tumor formation in aged animals
- Increased aneuploidy inhibits chemically and genetically induced tumorigenesis
- Aneuploid tumors inactivate Stat1 signaling with increased Myc activity
- Extra centrosomes correlate with chromosomal instability in tumors
- Stat1 loss combined with Myc activation alleviates CIN-induced immune infiltration
- CIN exists independently of classic mitotic defects in most cells
- Single-cell sequencing reveals karyotype heterogeneity in lymphomas
- Aneuploidy exhibits dual roles as oncogenic and tumor-suppressive
- CIN causality toward aneuploidy was previously unanswered
- Elevated merotely generates CIN in stable near-diploid cells
- Missegregation alone insufficient for aneuploid cell propagation