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Leukotriene D4 mediates survival and proliferation via separate but parallel pathways in the human intestinal Epithelial cell line Int 407.

Paruchuri, Sailaja LU and Sjölander, Anita LU (2003) In Journal of Biological Chemistry 278(46). p.45577-45585
Abstract
We demonstrated previously that leukotriene D-4 (LTD4) regulates proliferation of intestinal epithelial cells through a CysLT receptor by protein kinase C (PKC)epsilon-dependent stimulation of the mitogen-activated protein kinase ERK1/2. Our current study provides the first evidence that LTD4 can activate 90-kDa ribosomal S6 kinase (p90(RSK)) and cAMP-responsive element-binding protein (CREB) via pertussis-toxin-sensitive G(i) protein pathways. Transfection and inhibitor experiments revealed that activation of p90(RSK), but not CREB, is a PKCepsilon/Raf-1/ERK1/2-dependent process. LTD4-mediated CREB activation was not affected by expression of kinase-dead p90(RSK) but was abolished by transfection with the regulatory domain of PKCalpha (a... (More)
We demonstrated previously that leukotriene D-4 (LTD4) regulates proliferation of intestinal epithelial cells through a CysLT receptor by protein kinase C (PKC)epsilon-dependent stimulation of the mitogen-activated protein kinase ERK1/2. Our current study provides the first evidence that LTD4 can activate 90-kDa ribosomal S6 kinase (p90(RSK)) and cAMP-responsive element-binding protein (CREB) via pertussis-toxin-sensitive G(i) protein pathways. Transfection and inhibitor experiments revealed that activation of p90(RSK), but not CREB, is a PKCepsilon/Raf-1/ERK1/2-dependent process. LTD4-mediated CREB activation was not affected by expression of kinase-dead p90(RSK) but was abolished by transfection with the regulatory domain of PKCalpha (a specific dominant-inhibitor of PKCalpha). Kinase-negative mutants of p90(RSK) and CREB (K(-)p90(RSK) and K-CREB) blocked the LTD4-induced increase in cell number and DNA synthesis (thymidine incorporation). Compatible with these results, flow cytometry showed that LTD4 caused transition from the G(0)/G(1) to the S+G(2)/M cell cycle phase, indicating increased proliferation. Similar treatment of cells transfected with K-p90(RSK) resulted in cell cycle arrest in the G(0)/G(1) phase, consistent with a role of p90(RSK) in LTD4-induced proliferation. On the other hand, expression of K-CREB caused a substantial buildup in the sub-G(0)/G(1) phase, suggesting a role for CREB in mediating LTD4-mediated survival in intestinal epithelial cells. Our results show that LTD4 regulates proliferation and survival via distinct intracellular signaling pathways in intestinal epithelial cells. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
278
issue
46
pages
45577 - 45585
publisher
ASBMB
external identifiers
  • wos:000186452300066
  • scopus:0242413115
ISSN
1083-351X
DOI
10.1074/jbc.M302881200
language
English
LU publication?
yes
id
7f0499c9-9e4c-49e2-bca6-59ee5daf73ec (old id 117397)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12912998&dopt=Abstract
date added to LUP
2007-07-26 14:26:14
date last changed
2018-05-29 11:02:29
@article{7f0499c9-9e4c-49e2-bca6-59ee5daf73ec,
  abstract     = {We demonstrated previously that leukotriene D-4 (LTD4) regulates proliferation of intestinal epithelial cells through a CysLT receptor by protein kinase C (PKC)epsilon-dependent stimulation of the mitogen-activated protein kinase ERK1/2. Our current study provides the first evidence that LTD4 can activate 90-kDa ribosomal S6 kinase (p90(RSK)) and cAMP-responsive element-binding protein (CREB) via pertussis-toxin-sensitive G(i) protein pathways. Transfection and inhibitor experiments revealed that activation of p90(RSK), but not CREB, is a PKCepsilon/Raf-1/ERK1/2-dependent process. LTD4-mediated CREB activation was not affected by expression of kinase-dead p90(RSK) but was abolished by transfection with the regulatory domain of PKCalpha (a specific dominant-inhibitor of PKCalpha). Kinase-negative mutants of p90(RSK) and CREB (K(-)p90(RSK) and K-CREB) blocked the LTD4-induced increase in cell number and DNA synthesis (thymidine incorporation). Compatible with these results, flow cytometry showed that LTD4 caused transition from the G(0)/G(1) to the S+G(2)/M cell cycle phase, indicating increased proliferation. Similar treatment of cells transfected with K-p90(RSK) resulted in cell cycle arrest in the G(0)/G(1) phase, consistent with a role of p90(RSK) in LTD4-induced proliferation. On the other hand, expression of K-CREB caused a substantial buildup in the sub-G(0)/G(1) phase, suggesting a role for CREB in mediating LTD4-mediated survival in intestinal epithelial cells. Our results show that LTD4 regulates proliferation and survival via distinct intracellular signaling pathways in intestinal epithelial cells.},
  author       = {Paruchuri, Sailaja and Sjölander, Anita},
  issn         = {1083-351X},
  language     = {eng},
  number       = {46},
  pages        = {45577--45585},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Leukotriene D4 mediates survival and proliferation via separate but parallel pathways in the human intestinal Epithelial cell line Int 407.},
  url          = {http://dx.doi.org/10.1074/jbc.M302881200},
  volume       = {278},
  year         = {2003},
}