Subcellular localisation of Cdc25A determines cell fate.
Cell division cycle 25A (Cdc25A) was shown to colocalise both with nuclear and cytoplasmic proteins. Recently, we have demonstrated that overexpressed Cdc25A promoted the survival of rat 423 cells through indirect activation of PKB-protein kinase B. Using a Cdc25A:ER fusion protein, which can be shuttled from the cytoplasm into the nucleus, the present investigation evidences that the antiapoptotic effect of Cdc25A was restricted to its cytoplasmic localisation in rat 423 cells. In contrast, nuclear Cdc25A overexpression caused dephosphorylation and nuclear retention of the proapoptotic transcription factor Forkhead in rhabdomyosarcoma-like 1 (FKHRL1) in human N.1 ovarian carcinoma cells. This resulted in the increased constitutive expression of the FKHRL1 targets Fas ligand and Bim, and promoted apoptosis. Thus, the Cdc25A oncogene, which was found to be frequently overexpressed in certain human cancers, can increase or decrease the susceptibility to apoptosis depending on the cell-type-specific subcellular distribution.
Leisser
C
C
Institute of Clinical Pathology, University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria.
Rosenberger
G
G
Maier
S
S
Fuhrmann
G
G
Grusch
M
M
Strasser
S
S
Huettenbrenner
S
S
Fassl
S
S
Polgar
D
D
Krieger
S
S
Cerni
C
C
Hofer-Warbinek
R
R
deMartin
R
R
Krupitza
G
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D019677:Artificial Gene Fusion; D002451:Cell Compartmentation; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005822:Genetic Vectors; D006801:Humans; D009419:Nerve Tissue Proteins; D051381:Rats; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014170:Transformation, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C499515:FOXO3 protein, rat; C108803:FOXO4 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C107914:estrogen receptor-related receptor beta; C074639:Foxo1 protein, rat; C517004:CDC25A protein, human; C517007:Cdc25a protein, rat; D020687:cdc25 Phosphatases