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Ubiquitin-Conjugating Enzyme 3 Delays Human Lens Epithelial Cells in Metaphase

¹From the Laboratory for Nutrition and Vision Research, JMUSDA-HNRCA at Tufts University, Boston, Massachusetts; and the ²Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida.

PURPOSE. Ubc3/Cdc34 is a ubiquitin-conjugating enzyme (Ubc) with well established functions in the G₁-to-S-phase transition. Expecting to find similar effects in human lens epithelial cells (HLECs), the authors explored roles for this ubiquitin-conjugating enzyme in regulation of the HLEC cycle.

METHODS. Catalytically incompetent Ubc3 (C88S, L97S), wild-type (wt)Ubc3, and mutant (mt)Ubc2 (C93A) were expressed in HLECs, by using an adenoviral vector, and cell cycle progression was assessed.

RESULTS. Expression of mt- and wtUbc3, but not empty virus or mtUbc2, delayed the cell cycle in metaphase, rather than the expected G₁ phase. Expression of both Ubc3s also stabilized M-phase regulators, cyclin A, cyclin B, and securin. Thus, it appeared that the Ubc3 enzymes were playing roles different from canonical proteolytic functions in targeting G₁/S regulators for degradation. We also directly investigated the effect of inhibiting the proteasome on the cell cycle of HLECs. When the proteasome inhibitor was added to S-phase cells, the M-phase regulators were stabilized, and the cells were arrested in the G₂/M phase. In contrast, if the proteasome inhibitor was added before the cells entered the S phase, stabilization of the G₁ kinase inhibitors p21^WAF and p27^KIP was observed and the cells were arrested in the G₁ phase.

CONCLUSIONS. The ubiquitin-proteasome pathway is involved in regulation of transitions between all phases of the HLEC cycle. However, in contrast with previously described roles for Ubc3 in governing G₁/S transitions, expression of Ubc3 delays the HLEC cycle in metaphase. The data suggest novel roles for Ubc3 that do not involve the transfer of ubiquitin in the M phase in the HLEC cell cycle.

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