PMID- 22277942
OWN - NLM
STAT- MEDLINE
DCOM- 20120521
LR  - 20211021
IS  - 1523-1747 (Electronic)
IS  - 0022-202X (Print)
IS  - 0022-202X (Linking)
VI  - 132
IP  - 4
DP  - 2012 Apr
TI  - SERCA2-controlled Ca(2)+-dependent keratinocyte adhesion and differentiation is 
      mediated via the sphingolipid pathway: a therapeutic target for Darier's disease.
PG  - 1188-95
LID - 10.1038/jid.2011.447 [doi]
AB  - Darier's disease (DD), caused by mutations in the endoplasmic reticulum (ER) 
      Ca(2+) ATPase ATP2A2 (SERCA2b), is a skin disease that exhibits impaired 
      epidermal cell-to-cell adhesion and altered differentiation. Although previous 
      studies have shown that keratinocyte Ca(2+) sequestration and fluxes are 
      controlled by sphingolipid signaling, the role of this signaling pathway in DD 
      previously has not been investigated. We show here that sphingosine levels 
      increase and sphingosine kinase (SPHK1) expression decreases after inactivating 
      SERCA2b with the specific SERCA2 inhibitors thapsigargin (TG) or small 
      interfering RNA to SERCA2b. Conversely, inhibiting sphingosine lyase rescues the 
      defects in keratinocyte differentiation, E-cadherin localization, desmoplakin 
      (DP) translocation, and ER Ca(2+) sequestration seen in TG-treated keratinocytes. 
      Here, we report early evidence that the keratinocyte sphingolipid and Ca(2+) 
      signaling pathways intersect in ATP2A2-controlled ER Ca(2+) sequestration, 
      E-cadherin and DP localization, and Ca(2+)-controlled differentiation, and thus 
      may be important mediators in DD.
FAU - Celli, Anna
AU  - Celli A
AD  - Department of Dermatology, San Francisco Veterans Administration Medical Center, 
      San Francisco, California 94121-1545, USA. celli.anna@gmail.com
FAU - Mackenzie, Donald S
AU  - Mackenzie DS
FAU - Zhai, Yongjiao
AU  - Zhai Y
FAU - Tu, Chia-Ling
AU  - Tu CL
FAU - Bikle, Daniel D
AU  - Bikle DD
FAU - Holleran, Walter M
AU  - Holleran WM
FAU - Uchida, Yoshikazu
AU  - Uchida Y
FAU - Mauro, Theodora M
AU  - Mauro TM
LA  - eng
GR  - R01 AR051930/AR/NIAMS NIH HHS/United States
GR  - R01 AR050023/AR/NIAMS NIH HHS/United States
GR  - R01 AR051930-04/AR/NIAMS NIH HHS/United States
GR  - I01 BX001066/BX/BLRD VA/United States
GR  - R01 AR051930-03/AR/NIAMS NIH HHS/United States
GR  - R01 AR051930-02/AR/NIAMS NIH HHS/United States
GR  - R01 AR062025/AR/NIAMS NIH HHS/United States
GR  - AR051930/AR/NIAMS 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 - 20120126
PL  - United States
TA  - J Invest Dermatol
JT  - The Journal of investigative dermatology
JID - 0426720
RN  - 0 (Cadherins)
RN  - 0 (Desmoplakins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Sphingolipids)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.- (sphingosine kinase)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
RN  - EC 7.2.2.10 (ATP2A2 protein, human)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Cadherins/metabolism
MH  - Calcium/*physiology
MH  - Calcium Signaling/drug effects/physiology
MH  - Cell Adhesion/drug effects/physiology
MH  - Cell Differentiation/drug effects/*physiology
MH  - Cells, Cultured
MH  - Darier Disease/drug therapy/*physiopathology
MH  - Desmoplakins/metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - Keratinocytes/drug effects/metabolism/*pathology
MH  - Mutation/genetics
MH  - Phosphotransferases (Alcohol Group Acceptor)/metabolism
MH  - RNA, Small Interfering/pharmacology
MH  - Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & 
      inhibitors/genetics/*physiology
MH  - Signal Transduction/*physiology
MH  - Sphingolipids/*physiology
MH  - Thapsigargin/pharmacology
PMC - PMC3305850
MID - NIHMS343277
COIS- Conflict of interest: The authors have no conflict of interest.
EDAT- 2012/01/27 06:00
MHDA- 2012/05/23 06:00
PMCR- 2012/10/01
CRDT- 2012/01/27 06:00
PHST- 2012/01/27 06:00 [entrez]
PHST- 2012/01/27 06:00 [pubmed]
PHST- 2012/05/23 06:00 [medline]
PHST- 2012/10/01 00:00 [pmc-release]
AID - S0022-202X(15)35698-0 [pii]
AID - 10.1038/jid.2011.447 [doi]
PST - ppublish
SO  - J Invest Dermatol. 2012 Apr;132(4):1188-95. doi: 10.1038/jid.2011.447. Epub 2012 
      Jan 26.