PMID- 21205828
OWN - NLM
STAT- MEDLINE
DCOM- 20110504
LR  - 20211020
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 286
IP  - 9
DP  - 2011 Mar 4
TI  - Cullin-4A.DNA damage-binding protein 1 E3 ligase complex targets tumor suppressor 
      RASSF1A for degradation during mitosis.
PG  - 6971-8
LID - 10.1074/jbc.M110.186494 [doi]
AB  - Tumor suppressor RASSF1A (RAS association domain family 1, isoform A) is known to 
      play an important role in regulation of mitosis; however, little is known about 
      how RASSF1A is regulated during the mitotic phase of the cell cycle. In the 
      present study, we have identified Cullin-4A (CUL4A) as a novel E3 ligase for 
      RASSF1A. Our results demonstrate that DNA damage-binding protein 1 (DDB1) 
      functions as a substrate adaptor that directly interacts with RASSF1A and bridges 
      RASSF1A to the CUL4A E3 ligase complex. Depletion of DDB1 also diminishes 
      intracellular interactions between RASSF1A and CUL4A. Our results also show that 
      RASSF1A interacts with DDB1 via a region containing amino acids 165-200, and 
      deletion of this region abolishes RASSF1A and DDB1 interactions. We have found 
      that CUL4A depletion results in increased levels of RASSF1A protein due to 
      increased half-life; whereas overexpression of CUL4A and DDB1 markedly enhances 
      RASSF1A protein ubiquitination resulting in reduced RASSF1A levels. We further 
      show that CUL4A-mediated RASSF1A degradation occurs during mitosis, and depletion 
      of CUL4A markedly reverses mitotic-phase-stimulated RASSF1A degradation. We also 
      note that overexpression of CUL4A antagonizes the ability of RASSF1A to induce 
      M-phase cell cycle arrest. Thus, our present study demonstrates that the 
      CUL4A.DDB1 E3 complex is important for regulation of RASSF1A during mitosis, and 
      it may contribute to inactivation of RASSF1A and promoting cell cycle 
      progression.
FAU - Jiang, Lingyan
AU  - Jiang L
AD  - Department of Pharmacology, State University of New York, Upstate Medical 
      University, Syracuse, New York 13210, USA.
FAU - Rong, Rong
AU  - Rong R
FAU - Sheikh, M Saeed
AU  - Sheikh MS
FAU - Huang, Ying
AU  - Huang Y
LA  - eng
GR  - R03 CA128096/CA/NCI NIH HHS/United States
GR  - R21 CA113868/CA/NCI NIH HHS/United States
GR  - CA128096/CA/NCI NIH HHS/United States
GR  - CA113868/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20110104
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (CUL4A protein, human)
RN  - 0 (Cullin Proteins)
RN  - 0 (DDB1 protein, human)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (RASSF1 protein, human)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - Breast Neoplasms
MH  - Cell Line, Tumor
MH  - Cullin Proteins/genetics/*metabolism
MH  - DNA Damage/*physiology
MH  - DNA-Binding Proteins/chemistry/*metabolism
MH  - Female
MH  - HEK293 Cells
MH  - Humans
MH  - Mitosis/*physiology
MH  - Multiprotein Complexes/metabolism
MH  - Protein Stability
MH  - Protein Structure, Tertiary
MH  - RNA Interference
MH  - Tumor Suppressor Proteins/chemistry/genetics/*metabolism
MH  - Ubiquitin-Protein Ligases/genetics/metabolism
MH  - Ubiquitination/physiology
PMC - PMC3044953
EDAT- 2011/01/06 06:00
MHDA- 2011/05/05 06:00
PMCR- 2012/03/04
CRDT- 2011/01/06 06:00
PHST- 2011/01/06 06:00 [entrez]
PHST- 2011/01/06 06:00 [pubmed]
PHST- 2011/05/05 06:00 [medline]
PHST- 2012/03/04 00:00 [pmc-release]
AID - S0021-9258(20)51891-7 [pii]
AID - M110.186494 [pii]
AID - 10.1074/jbc.M110.186494 [doi]
PST - ppublish
SO  - J Biol Chem. 2011 Mar 4;286(9):6971-8. doi: 10.1074/jbc.M110.186494. Epub 2011 
      Jan 4.