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2015 ; 128
(22
): 4171-82
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A new mitochondrial pool of cyclin E, regulated by Drp1, is linked to
cell-density-dependent cell proliferation
#MMPMID26446260
Parker DJ
; Iyer A
; Shah S
; Moran A
; Hjelmeland AB
; Basu MK
; Liu R
; Mitra K
J Cell Sci
2015[Nov]; 128
(22
): 4171-82
PMID26446260
show ga
The regulation and function of the crucial cell cycle regulator cyclin E (CycE)
remains elusive. Unlike other cyclins, CycE can be uniquely controlled by
mitochondrial energetics, the exact mechanism being unclear. Using mammalian
cells (in vitro) and Drosophila (in vivo) model systems in parallel, we show that
CycE can be directly regulated by mitochondria through its recruitment to the
organelle. Active mitochondrial bioenergetics maintains a distinct mitochondrial
pool of CycE (mtCycE) lacking a key phosphorylation required for its degradation.
Loss of the mitochondrial fission protein dynamin-related protein 1 (Drp1,
SwissProt O00429 in humans) augments mitochondrial respiration and elevates the
mtCycE pool allowing CycE deregulation, cell cycle alterations and enrichment of
stem cell markers. Such CycE deregulation after Drp1 loss attenuates cell
proliferation in low-cell-density environments. However, in high-cell-density
environments, elevated MEK-ERK signaling in the absence of Drp1 releases mtCycE
to support escape of contact inhibition and maintain aberrant cell proliferation.
Such Drp1-driven regulation of CycE recruitment to mitochondria might be a
mechanism to modulate CycE degradation during normal developmental processes as
well as in tumorigenic events.