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. 2012 Dec;1820(12):1893-900.
doi: 10.1016/j.bbagen.2012.08.002. Epub 2012 Aug 10.

Depletion of SUMO ligase hMMS21 impairs G1 to S transition in MCF-7 breast cancer cells

Huey-Juin Ni  1 , Ying-Nang Chang, Pu-Hong Kao, Shin-Pei Chai, Ya-Hsin Hsieh, Duo-Hsiang Wang, Jim C Fong
Affiliations

Depletion of SUMO ligase hMMS21 impairs G1 to S transition in MCF-7 breast cancer cells

Huey-Juin Ni et al. Biochim Biophys Acta. 2012 Dec.

Abstract

Background: hMMS21 is a human SUMO ligase required for DNA damage repair and mitotic progression in HeLa cervical cancer cells. Owing to the diversity of cancer, we further investigated the effect of hMMS21-depletion on MCF-7 breast cancer cells.

Methods: hMMS21-depletion was achieved by RNA interference. Cellular hMMS21 and E2F1 mRNA levels were estimated by RT-PCR and real-time PCR. Cell cycle profile was assessed by flow cytometry. Western blot and co-immunoprecipitation were used to determine the protein levels of various factors involved in G1-S transition and CDK2- or CDK4-associated p21 and p27. Kinase activity of cyclin E/CDK2 was measured in anti-cyclin E immunoprecipitate.

Results: hMMS21-depletion induced slower cell growth and G1-S transition. While it had no effect on cyclin D1 or phospho-Rb (S807/811) levels, hMMS21-depletion provoked lower E2F1 levels and cyclin E/CDK2 activity. The decreased cyclin E/CDK2 activity correlated with increased cellular p21(CIP1) levels and CDK2-p21 association. Moreover, ectopic expression of Flag-hMMS21 but not its ligase-inactive mutant rescued the decreased growth rates of hMMS21-depletd cells. Thus, depletion of hMMS21 seems to impair G1-S transition due to lowered E2F1 protein levels and cyclin E/CDK2 activity. The decreased cyclin E/CDK2 activity is probably attributable to its greater association with p21 as a result of increased p21 levels. In addition, hMMS21-mediated sumoylation appears to be involved.

General significance: This study demonstrates that hMMS21 is required for G1-S transition in breast cancer cells and implies that manipulation of hMMS21-mediated sumoylation may alter the growth rates of breast cancer cells.

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