PMID- 22094461
OWN - NLM
STAT- MEDLINE
DCOM- 20120508
LR  - 20211203
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 287
IP  - 1
DP  - 2012 Jan 2
TI  - Phospholipase D2 (PLD2) shortens the time required for myeloid leukemic cell 
      differentiation: mechanism of action.
PG  - 393-407
LID - S0021-9258(20)53522-9 [pii]
LID - 10.1074/jbc.M111.259465 [doi]
AB  - Cell differentiation is compromised in acute leukemias. We report that mammalian 
      target of rapamycin (mTOR) and S6 kinase (S6K) are highly expressed in the 
      undifferentiated promyelomonocytic leukemic HL-60 cell line, whereas PLD2 
      expression is minimal. The expression ratio of PLD2 to mTOR (or to S6K) is 
      gradually inverted upon in vitro induction of differentiation toward the 
      neutrophilic phenotype. We present three ways that profoundly affect the kinetics 
      of differentiation as follows: (i) simultaneous overexpression of mTOR (or S6K), 
      (ii) silencing of mTOR via dsRNA-mediated interference or inhibition with 
      rapamycin, and (iii) PLD2 overexpression. The last two methods shortened the time 
      required for differentiation. By determining how PLD2 participates in cell 
      differentiation, we found that PLD2 interacts with and activates the oncogene 
      Fes/Fps, a protein-tyrosine kinase known to be involved in myeloid cell 
      development. Fes activity is elevated with PLD2 overexpression, phosphatidic acid 
      or phosphatidylinositol bisphosphate. Co-immunoprecipitation indicates a close 
      PLD2-Fes physical interaction that is negated by a Fes-R483K mutant that 
      incapacitates its Src homology 2 domain. All these suggest for the first time the 
      following mechanism: mTOR/S6K down-regulation-->PLD2 overexpression-->PLD2/Fes 
      association-->phosphatidic acid-led activation of Fes kinase-->granulocytic 
      differentiation. Differentiation shortening could have a clinical impact on 
      reducing the time of return to normalcy of the white cell counts after 
      chemotherapy in patients with acute promyelocytic leukemia.
FAU - Di Fulvio, Mauricio
AU  - Di Fulvio M
AD  - Department of Biochemistry and Molecular Biology, Wright State University School 
      Medicine, Dayton, Ohio, 45435.
FAU - Frondorf, Kathleen
AU  - Frondorf K
AD  - Department of Biochemistry and Molecular Biology, Wright State University School 
      Medicine, Dayton, Ohio, 45435.
FAU - Henkels, Karen M
AU  - Henkels KM
AD  - Department of Biochemistry and Molecular Biology, Wright State University School 
      Medicine, Dayton, Ohio, 45435.
FAU - Grunwald, William C Jr
AU  - Grunwald WC Jr
AD  - Department of Pharmacology and Toxicology, Wright State University School 
      Medicine, Dayton, Ohio 45435.
FAU - Cool, David
AU  - Cool D
AD  - Department of Pharmacology and Toxicology, Wright State University School 
      Medicine, Dayton, Ohio 45435.
FAU - Gomez-Cambronero, Julian
AU  - Gomez-Cambronero J
AD  - Department of Biochemistry and Molecular Biology, Wright State University School 
      Medicine, Dayton, Ohio, 45435. Electronic address: julian.cambronero@wright.edu.
LA  - eng
GR  - R01 HL056653/HL/NHLBI NIH HHS/United States
GR  - R29 HL056653/HL/NHLBI NIH HHS/United States
GR  - HL056653/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111117
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (RNA, Messenger)
RN  - EC 2.7.10.2 (FES protein, human)
RN  - EC 2.7.10.2 (Proto-Oncogene Proteins c-fes)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.4.- (phospholipase D2)
RN  - EC 3.1.4.4 (Phospholipase D)
SB  - IM
MH  - Base Sequence
MH  - *Cell Differentiation/drug effects/genetics
MH  - Enzyme Activation/drug effects/genetics
MH  - Gene Silencing
MH  - HL-60 Cells
MH  - Humans
MH  - Kinetics
MH  - Leukemia, Myeloid/*pathology
MH  - Molecular Sequence Data
MH  - Phospholipase D/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-fes/chemistry/metabolism
MH  - RNA, Messenger/genetics/metabolism
MH  - Ribosomal Protein S6 Kinases/genetics/metabolism
MH  - TOR Serine-Threonine Kinases/antagonists & 
      inhibitors/deficiency/genetics/metabolism
MH  - Up-Regulation/drug effects/genetics
MH  - src Homology Domains
PMC - PMC3249091
EDAT- 2011/11/19 06:00
MHDA- 2012/05/09 06:00
PMCR- 2013/01/02
CRDT- 2011/11/19 06:00
PHST- 2011/11/19 06:00 [entrez]
PHST- 2011/11/19 06:00 [pubmed]
PHST- 2012/05/09 06:00 [medline]
PHST- 2013/01/02 00:00 [pmc-release]
AID - S0021-9258(20)53522-9 [pii]
AID - M111.259465 [pii]
AID - 10.1074/jbc.M111.259465 [doi]
PST - ppublish
SO  - J Biol Chem. 2012 Jan 2;287(1):393-407. doi: 10.1074/jbc.M111.259465. Epub 2011 
      Nov 17.