Acetylation-dependent regulation of Skp2 function Journal Article
| Authors: | Inuzuka, H.; Gao, D.; Finley, L. W. S.; Yang, W.; Wan, L.; Fukushima, H.; Chin, Y. R.; Zhai, B.; Shaik, S.; Lau, A. W.; Wang, Z.; Gygi, S. P.; Nakayama, K.; Teruya-Feldstein, J.; Toker, A.; Haigis, M. C.; Pandolfi, P. P.; Wei, W. |
| Article Title: | Acetylation-dependent regulation of Skp2 function |
| Abstract: | Aberrant Skp2 signaling has been implicated as a driving event in tumorigenesis. Although the underlying molecular mechanisms remain elusive, cytoplasmic Skp2 correlates with more aggressive forms of breast and prostate cancers. Here, we report that Skp2 is acetylated by p300 at K68 and K71, which is a process that can be antagonized by the SIRT3 deacetylase. Inactivation of SIRT3 leads to elevated Skp2 acetylation, which leads to increased Skp2 stability through impairment of the Cdh1-mediated proteolysis pathway. As a result, Skp2 oncogenic function is increased, whereby cells expressing an acetylation-mimetic mutant display enhanced cellular proliferation and tumorigenesis in vivo. Moreover, acetylation of Skp2 in the nuclear localization signal (NLS) promotes its cytoplasmic retention, and cytoplasmic Skp2 enhances cellular migration through ubiquitination and destruction of E-cadherin. Thus, our study identifies an acetylation-dependent regulatory mechanism governing Skp2 oncogenic function and provides insight into how cytoplasmic Skp2 controls cellular migration. © 2012 Elsevier Inc. |
| Keywords: | signal transduction; controlled study; protein expression; protein phosphorylation; human cell; nonhuman; protein function; protein localization; cell proliferation; animal cell; mouse; animals; mice; animal tissue; protein degradation; protein protein interaction; animal experiment; animal model; protein stability; cell line, tumor; breast neoplasms; uvomorulin; carcinogenesis; prostatic neoplasms; ubiquitination; amino acid sequence; molecular sequence data; protein processing, post-translational; sequence alignment; cell migration; cell movement; cytoplasm; disease models, animal; cadherins; nuclear localization signal; lysine; s phase kinase associated protein 2; s-phase kinase-associated proteins; acetylation; protein p300; p300-cbp transcription factors; sirtuin 3; casein kinase i; protein sorting signals |
| Journal Title: | Cell |
| Volume: | 150 |
| Issue: | 1 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2012-07-06 |
| Start Page: | 179 |
| End Page: | 193 |
| Language: | English |
| DOI: | 10.1016/j.cell.2012.05.038 |
| PROVIDER: | scopus |
| PUBMED: | 22770219 |
| PMCID: | PMC3595190 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 August 2012" - "CODEN: CELLB" - "Source: Scopus" |
