PMID- 18273051
OWN - NLM
STAT- MEDLINE
DCOM- 20080829
LR  - 20211203
IS  - 1523-1747 (Electronic)
IS  - 0022-202X (Linking)
VI  - 128
IP  - 8
DP  - 2008 Aug
TI  - TNF-alpha impairs the S-G2/M cell cycle checkpoint and cyclobutane pyrimidine 
      dimer repair in premalignant skin cells: role of the PI3K-Akt pathway.
PG  - 2069-77
LID - 10.1038/jid.2008.19 [doi]
AB  - Tumor necrosis factor-alpha (TNF-alpha) is induced by UVB radiation and has been 
      implicated in the early stages of skin carcinogenesis. Here, we show that in 
      normal keratinocytes and the transformed keratinocyte cell lines, HaCaT and A431, 
      TNF-alpha stimulates protein kinase B/Akt, which results in activation of the 
      survival complex mTORC1 (mammalian target of rapamycin complex 1) and inhibition 
      of the proapoptotic proteins Bad and FoxO3a. In UVB-irradiated HaCaT cells (10-20 
      mJ cm(-2)), TNF-alpha increased the proportion of cycling cells and enhanced the 
      rate of apoptosis. A significantly higher proportion of UVB-treated HaCaT cells 
      containing unrepaired cyclobutane pyrimidine dimers (CPDs) escaped the G2/M cell 
      cycle checkpoint in the presence of TNF-alpha (9.5+/-3.3 vs 4.8+/-2.2%). After 
      treatment with the PI3K inhibitor LY294002, only 1.2+/-0.7% of CPD-containing 
      HaCaT cells were actively cycling. TNF-alpha enhanced apoptosis less potently and 
      did not increase the level of CPD or stimulate cell cycle progression in normal 
      keratinocytes. Our data suggest that TNF-alpha overrides the G2/M checkpoint in 
      premalignant skin cells and allows for some cells containing unrepaired CPD to 
      enter the cell cycle. The effect of TNF-alpha seems to be dependent on Akt 
      activation and may constitute a relevant mechanism enhancing mutagenesis and 
      tumor development.
FAU - Faurschou, Annesofie
AU  - Faurschou A
AD  - Department of Dermatology, University of Copenhagen, Bispebjerg Hospital, 
      Copenhagen, Denmark. Af16@bbh.regionh.dk
FAU - Gniadecki, Robert
AU  - Gniadecki R
FAU - Calay, Damien
AU  - Calay D
FAU - Wulf, Hans Christian
AU  - Wulf HC
LA  - eng
PT  - Journal Article
DEP - 20080214
PL  - United States
TA  - J Invest Dermatol
JT  - The Journal of investigative dermatology
JID - 0426720
RN  - 0 (BAD protein, human)
RN  - 0 (Chromones)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (FOXO3 protein, human)
RN  - 0 (Forkhead Box Protein O3)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Morpholines)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
RN  - 0 (Pyrimidine Dimers)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (bcl-Associated Death Protein)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 9007-49-2 (DNA)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Oncogene Protein v-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Cell Cycle/drug effects
MH  - Cell Line
MH  - Cell Proliferation
MH  - Cell Survival
MH  - Chromones/pharmacology
MH  - DNA/genetics
MH  - DNA Repair/*genetics
MH  - Enzyme Inhibitors/pharmacology
MH  - Forkhead Box Protein O3
MH  - Forkhead Transcription Factors/metabolism
MH  - *Genes, cdc
MH  - Humans
MH  - Keratinocytes/metabolism/*pathology/radiation effects
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Morpholines/pharmacology
MH  - Multiprotein Complexes
MH  - Oncogene Protein v-akt/*metabolism
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Precancerous Conditions/genetics/metabolism/pathology
MH  - Proteins
MH  - Pyrimidine Dimers/*genetics
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/metabolism
MH  - Tumor Necrosis Factor-alpha/*metabolism
MH  - bcl-Associated Death Protein/metabolism
EDAT- 2008/02/15 09:00
MHDA- 2008/08/30 09:00
CRDT- 2008/02/15 09:00
PHST- 2008/02/15 09:00 [pubmed]
PHST- 2008/08/30 09:00 [medline]
PHST- 2008/02/15 09:00 [entrez]
AID - S0022-202X(15)33994-4 [pii]
AID - 10.1038/jid.2008.19 [doi]
PST - ppublish
SO  - J Invest Dermatol. 2008 Aug;128(8):2069-77. doi: 10.1038/jid.2008.19. Epub 2008 
      Feb 14.