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.
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Hiroyuki
authors: H
authors: Inuzuka
authors: Daming
authors: D
authors: Gao
authors: Lydia W S
authors: LW
authors: Finley
authors: Wen
authors: W
authors: Yang
authors: Lixin
authors: L
authors: Wan
authors: Hidefumi
authors: H
authors: Fukushima
authors: Y Rebecca
authors: YR
authors: Chin
authors: Bo
authors: B
authors: Zhai
authors: Shavali
authors: S
authors: Shaik
authors: Alan W
authors: AW
authors: Lau
authors: Zhiwei
authors: Z
authors: Wang
authors: Steven P
authors: SP
authors: Gygi
authors: Keiko
authors: K
authors: Nakayama
authors: Julie
authors: J
authors: Teruya-Feldstein
authors: Alex
authors: A
authors: Toker
authors: Marcia C
authors: MC
authors: Haigis
authors: Pier Paolo
authors: PP
authors: Pandolfi
authors: Wenyi
authors: W
authors: Wei
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D047389:Casein Kinase I / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011499:Protein Processing, Post-Translational; D021382:Protein Sorting Signals; D044786:S-Phase Kinase-Associated Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D054875:Ubiquitination; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D015820:Cadherins; D047389:Casein Kinase I; D008239:Lysine; D021382:Protein Sorting Signals; D044786:S-Phase Kinase-Associated Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor