PMID- 18790760
OWN - NLM
STAT- MEDLINE
DCOM- 20081022
LR  - 20211020
IS  - 1535-7163 (Print)
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Linking)
VI  - 7
IP  - 9
DP  - 2008 Sep
TI  - hKSR-2, a vitamin D-regulated gene, inhibits apoptosis in arabinocytosine-treated 
      HL60 leukemia cells.
PG  - 2798-806
LID - 10.1158/1535-7163.MCT-08-0276 [doi]
AB  - Ras signaling can be modulated by the scaffolding activity of kinase suppressor 
      of Ras-1 (KSR-1) and by the hKSR-2 protein, resulting in diverse phenotypic 
      outcomes. The mitogen-activated protein kinase cascade downstream from Ras and 
      KSRs includes Raf-1 and extracellular signal-regulated kinase 1/2 kinases, known 
      to enhance survival potential of a range of cell types. Because the molecular 
      events that increase survival of HL60 cells induced to differentiate toward 
      monocytic phenotype by 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] are not known, we 
      investigated if KSR proteins provide a survival function in these cells. We found 
      that whereas kinase suppressor of Ras-1 had no detectable effect on cell survival 
      in the system studied here, 1,25-(OH)2D3-induced up-regulation of hKSR-2 enhanced 
      the resistance of HL60 cells to arabinocytosine. Knockdown of hKSR-2 by either 
      small interfering RNA or antisense oligonucleotides increased 
      arabinocytosine-induced apoptosis, which was accompanied by reduced Bcl-2/Bax and 
      Bcl-2/Bad ratios, and increased caspase-3 activating cleavage. In contrast, 
      up-regulation of Mcl-1 was not abrogated by anti-sense (AS) AS-hKSR-2, pointing 
      to a specific role of Bcl-2 in control of 1,25-(OH)2D3-induced increased cell 
      survival. These findings are consistent with the previously shown lack of fully 
      differentiated monocytic cells in HL60 cultures exposed to 1,25-(OH)2D3 in which 
      hKSR-2 was knocked down, suggesting that optimal differentiation of these cells 
      requires enhanced antiapoptotic mechanisms provided, at least in part, by hKSR-2. 
      Collectively, these results suggest that hKSR-2 may offer a new target for novel 
      therapies of acute myelogenous leukemia.
FAU - Wang, Xuening
AU  - Wang X
AD  - Department of Pathology and Laboratory Medicine, University of Medicine and 
      Dentistry of New Jersey-New Jersey Medical School, 185 South Orange Avenue, 
      Newark, NJ 07103, USA.
FAU - Patel, Rahul
AU  - Patel R
FAU - Studzinski, George P
AU  - Studzinski GP
LA  - eng
GR  - R01-CA-117942-01/CA/NCI NIH HHS/United States
GR  - R01 CA117942/CA/NCI NIH HHS/United States
GR  - R01-CA-44722-18/CA/NCI NIH HHS/United States
GR  - R01 CA044722/CA/NCI NIH HHS/United States
GR  - R01 CA044722-10A1/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antioxidants)
RN  - 0 (CNKSR2 protein, human)
RN  - 0 (Myeloid Cell Leukemia Sequence 1 Protein)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (dihydroxy-vitamin D3)
RN  - 04079A1RDZ (Cytarabine)
RN  - 1406-16-2 (Vitamin D)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
MH  - Acetylcysteine/pharmacology
MH  - Adaptor Proteins, Signal Transducing/antagonists & 
      inhibitors/*genetics/metabolism
MH  - Antioxidants/pharmacology
MH  - Apoptosis/*drug effects
MH  - Cytarabine/*toxicity
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - HL-60 Cells
MH  - Humans
MH  - Myeloid Cell Leukemia Sequence 1 Protein
MH  - Necrosis
MH  - Oligonucleotides, Antisense/pharmacology
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - RNA, Messenger/genetics/metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Vitamin D/analogs & derivatives/*metabolism/pharmacology
PMC - PMC2814415
MID - NIHMS81080
COIS- Disclosure of Potential Conflicts of Interest: No potential conflicts of interest 
      were disclosed.
EDAT- 2008/09/16 09:00
MHDA- 2008/10/23 09:00
PMCR- 2010/02/01
CRDT- 2008/09/16 09:00
PHST- 2008/09/16 09:00 [pubmed]
PHST- 2008/10/23 09:00 [medline]
PHST- 2008/09/16 09:00 [entrez]
PHST- 2010/02/01 00:00 [pmc-release]
AID - 7/9/2798 [pii]
AID - 10.1158/1535-7163.MCT-08-0276 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2008 Sep;7(9):2798-806. doi: 10.1158/1535-7163.MCT-08-0276.