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Target Concepts:
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Query: UNIPROT:Q86TM3 (
cage
)
29,987
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Centrosomes catalyse the formation of microtubules needed to assemble the mitotic spindle apparatus
1
. Centrosomes themselves duplicate once per cell cycle, in a process that is controlled by the serine/threonine protein kinase PLK4 (refs.
2,3
). When PLK4 is chemically inhibited, cell division proceeds without centrosome duplication, generating centrosome-less cells that exhibit delayed, acentrosomal spindle assembly
4
. Whether PLK4 inhibitors can be leveraged as a treatment for cancer is not yet clear. Here we show that acentrosomal spindle assembly following PLK4 inhibition depends on levels of the centrosomal ubiquitin ligase
TRIM37
. Low
TRIM37
levels accelerate acentrosomal spindle assembly and improve proliferation following PLK4 inhibition, whereas high
TRIM37
levels inhibit acentrosomal spindle assembly, leading to mitotic failure and cessation of proliferation. The Chr17q region containing the
TRIM37
gene is frequently amplified in neuroblastoma and in breast cancer
5-8
, rendering these cancer types highly sensitive to PLK4 inhibition. We find that inactivating
TRIM37
improves acentrosomal mitosis because
TRIM37
prevents PLK4 from self-assembling into centrosome-independent condensates that serve as ectopic microtubule-organizing centres. By contrast, elevated
TRIM37
expression inhibits acentrosomal spindle assembly through a distinct mechanism that involves degradation of the centrosomal component CEP192. Thus,
TRIM37
is an essential determinant of mitotic vulnerability to PLK4 inhibition. Linkage of
TRIM37
to prevalent
cancer-associated
genomic changes-including 17q gain in neuroblastoma and 17q23 amplification in breast cancer-may offer an opportunity to use PLK4 inhibition to trigger selective mitotic failure and provide new avenues to treatments for these cancers.
...
PMID:TRIM37 controls cancer-specific vulnerability to PLK4 inhibition. 3290 4
