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Whitcomb EA, Tsai YC, Basappa J, Liu K, Le Feuvre AK, Weissman AM, Taylor A
Stabilization of p27Kip1/CDKN1B by UBCH7/UBE2L3 catalyzed ubiquitinylation: A new paradigm in cell-cycle control
FASEB Journal (2019) 33:1235-1247.
Ubiquitinylation drives many cellular processes by targeting proteins for proteasomal degradation. Ubiquitin conjugation enzymes promote ubiquitinylation and, thus, degradation of protein substrates. Ubiquitinylation is a well-known posttranslational modification controlling cell-cycle transitions and levels or/and activation levels of ubiquitin-conjugating enzymes change during development and cell cycle. Progression through the cell cycle is tightly controlled by CDK inhibitors such as p27(Kip1). Here we show that, in contrast to promoting its degradation, the ubiquitin-conjugating enzyme UBCH7/UBE2L3 specifically protects p27(Kip1) from degradation. Overexpression of UBCH7/UBE2L3 stabilizes p27(Kip1) and delays the G1-to-S transition, while depletion of UBCH7/UBE2L3 increases turnover of p27(Kip1). Levels of p21(Cip1/Waf1), p57(Kip2), cyclin A and cyclin E, all of which are also involved in regulating the G1/S transition are not affected by UBCH7/UBE2L3 depletion. The effect of UBCH7/UBE2L3 on p27(Kip1) is not due to alteration of the levels of any of the ubiquitin ligases known to ubiquitinylate p27(Kip1). Rather, UBCH7/UBE2L3 catalyzes the conjugation of heterotypic ubiquitin chains on p27(Kip1) that are proteolytically incompetent. These data reveal new controls and concepts about the ubiquitin proteasome system in which a ubiquitin-conjugating enzyme selectively inhibits and may even protect, rather than promote degradation of a crucial cell-cycle regulatory molecule.-Whitcomb, E. A., Tsai, Y. C., Basappa, J., Liu, K., Le Feuvre, A. K., Weissman, A. M., Taylor, A. Stabilization of p27(Kip1)/CDKN1B by UBCH7/UBE2L3 catalyzed ubiquitinylation: a new paradigm in cell-cycle control.
Publication Date: 2019-01-01.
PMCID: PMC6355086
Last updated on Monday, May 04, 2020