Increased levels of transcription factors Elk-1, cyclic adenosine monophosphate response element-binding protein, and activating transcription factor 2 in the cerebellar vermis of schizophrenic patients.
BACKGROUND
We investigated the levels of transcription factors associated with activation of the mitogen-activated protein (MAP) kinase pathway in schizophrenics using postmortem brain samples. These studies were done to determine whether our previous findings of abnormal levels of the MAP kinases in the cerebellar vermis were linked to additional downstream targets of this signal transduction pathway.


METHODS
We measured the protein levels of 3 transcription factors in nuclear fractions of postmortem samples from cerebellar vermis of 10 patients with schizophrenia and 13 control subjects: Elk-1, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and activating transcription factor 2 (ATF-2). Studies in rats examined the postmortem stability and effect of haloperidol and risperidone on levels of Elk-1, cAMP, and ATF-2 proteins.


RESULTS
We found a significant increase in the protein levels of Elk-1 (mean+SD, 4489+/-659 vs 2915+/-583 arbitrary densitometric units [P<.001]), CREB (mean +/- SD, 2149 1061 vs 904+/-711 arbitrary densitometric units [P=.003]) and ATF-2 (mean+/-SD, 1421 854 vs 512+/-394 arbitrary densitometric units [P=.003]) in the cerebellar vermis of schizophrenic subjects. Complementary studies in rats indicate that these findings can not be attributed to subacute treatment with antipsychotic medications.


CONCLUSIONS
Taken together with the alterations of MAP kinases previously reported, and the findings of elevations of downstream transcription targets, we suggest that the MAP kinase signal transduction pathway contributes to the cerebellar abnormalities in schizophrenia.
Kyosseva
S V
SV
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, USA.
Elbein
A D
AD
Hutton
T L
TL
Griffin
S T
ST
Mrak
R E
RE
Sturner
W Q
WQ
Karson
C N
CN
D051698:Activating Transcription Factor 2; D000328:Adult; D000368:Aged; D000818:Animals; D002531:Cerebellum / Q000737:chemistry* / Q000201:enzymology / Q000378:metabolism; D002373:Cyclic AMP Receptor Protein / Q000032:analysis / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis / Q000378:metabolism; D004268:DNA-Binding Proteins; D005260:Female; D006220:Haloperidol / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000032:analysis / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism; D051381:Rats; D018967:Risperidone / Q000494:pharmacology / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000032:analysis* / Q000378:metabolism; D050807:ets-Domain Protein Elk-1
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C497107:Atf2 protein, rat; D002373:Cyclic AMP Receptor Protein; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; C494114:Elk1 protein, rat; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D020929:Mitogen-Activated Protein Kinase Kinases; D006220:Haloperidol; D018967:Risperidone