The expression of KLF11 (TIEG2), a monoamine oxidase B transcriptional activator in the prefrontal cortex of human alcohol dependence.

BACKGROUND The biochemical pathways underlying alcohol abuse and dependence are not well understood, although brain cell loss and neurotoxicity have been reported in subjects with alcohol dependence. Monoamine oxidase B (MAO B; an enzyme that catabolizes neurotransmitters such as dopamine) is consistently increased in this psychiatric illness. MAO B has been implicated in the pathogenesis of alcohol dependence and alcohol-induced brain neurotoxicity. Recently, the cell growth inhibitor protein, Kruppel-like factor 11 (KLF11), has been reported to be an MAO transcriptional activator. KLF11 is also known as TIEG2 (transforming growth factor-beta-inducible early gene 2) and mediates apoptotic cell death. This study investigates the protein expression of KLF11 and its relationship with MAO B using human postmortem prefrontal cortex from subjects with alcohol dependence. METHODS Twelve subjects with alcohol dependence and the respective psychiatrically normal control subjects were investigated. Expression of KLF11 and MAO B proteins in the prefrontal cortex was measured by Western blot analysis. Correlation studies involving KLF11 and MAO B protein expression were performed. Localization of KLF11 in the human prefrontal cortex was also determined by immunohistochemistry. RESULTS Levels of KLF11 protein were significantly increased by 44% (p < 0.03) in the postmortem prefrontal cortex of subjects with alcohol dependence as compared to age- and gender-matched, psychiatrically normal control subjects. Furthermore, KLF11 levels were significantly and positively correlated with both the increased MAO B protein levels and blood alcohol content in alcohol-dependent subjects. In addition, KLF11 protein expression was visualized in both neuronal and glial cells. CONCLUSIONS This novel study shows the important role of KLF11, an MAO transcriptional activator, in human alcohol dependence. It further supports that the KLF11-MAO B cell death cascade may contribute to chronic alcohol-induced brain damage. This argues a case for KLF11-MAO B inhibition as a novel therapeutic strategy that may impact this highly prevalent illness.

[1]  Sumera H Rizvi,et al.  Sequence-specific Recruitment of Heterochromatin Protein 1 via Interaction with Krüppel-like Factor 11, a Human Transcription Factor Involved in Tumor Suppression and Metabolic Diseases , 2012, The Journal of Biological Chemistry.

[2]  T. Zima,et al.  Alpe Adria Report 2010 – Conclusions and Recommendations for the Treatment of Alcohol Dependence , 2011, Front. Psychiatry.

[3]  G. Rajkowska,et al.  The Reduction of R1, a Novel Repressor Protein for Monoamine Oxidase A, in Major Depressive Disorder , 2011, Neuropsychopharmacology.

[4]  J. Miguel-Hidalgo,et al.  Ethanol Increases TIEG2–MAO B Cell Death Cascade in the Prefrontal Cortex of Ethanol-Preferring Rats , 2011, Neurotoxicity Research.

[5]  Michael R Bardsley,et al.  A functional family-wide screening of SP/KLF proteins identifies a subset of suppressors of KRAS-mediated cell growth. , 2011, The Biochemical journal.

[6]  H. Meltzer,et al.  A Novel Role for Glyceraldehyde-3-Phosphate Dehydrogenase and Monoamine Oxidase B Cascade in Ethanol-Induced Cellular Damage , 2010, Biological Psychiatry.

[7]  G. Siggins,et al.  Neurobiological mechanisms contributing to alcohol-stress-anxiety interactions. , 2009, Alcohol.

[8]  L. Friedman,et al.  Antagonist but not agonist labeling of serotonin-1A receptors is decreased in major depressive disorder. , 2009, Journal of psychiatric research.

[9]  X. Ou,et al.  Retinoic Acid Activates Monoamine Oxidase B Promoter in Human Neuronal Cells* , 2009, The Journal of Biological Chemistry.

[10]  J. Overholser,et al.  Assessment of depression and suicidal actions: agreement between suicide attempters and informant reports. , 2009, Suicide & life-threatening behavior.

[11]  Shawna K. Tazik,et al.  The Neuroprotective Effect of Antidepressant Drug via Inhibition of TIEG2-MAO B Mediated Cell Death. , 2008, Drug discoveries & therapeutics.

[12]  Bjoern Peters,et al.  Human TIEG2/KLF11 induces oligodendroglial cell death by downregulation of Bcl-XL expression , 2007, Journal of Neural Transmission.

[13]  T. Gress,et al.  The Tumor Suppressor KLF11 Mediates a Novel Mechanism in Transforming Growth Factor β–Induced Growth Inhibition That Is Inactivated in Pancreatic Cancer , 2006, Molecular Cancer Research.

[14]  Sylvain Houle,et al.  Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. , 2006, Archives of general psychiatry.

[15]  G. Rajkowska,et al.  Reduced glial and neuronal packing density in the orbitofrontal cortex in alcohol dependence and its relationship with suicide and duration of alcohol dependence. , 2006, Alcoholism, clinical and experimental research.

[16]  Keith F. Tipton,et al.  The therapeutic potential of monoamine oxidase inhibitors , 2006, Nature Reviews Neuroscience.

[17]  J. Kleinman,et al.  Reliability of psychiatric diagnosis in postmortem research , 2005, Biological Psychiatry.

[18]  A. Ravindran,et al.  MAO-A gene polymorphisms are associated with major depression and sleep disturbance in males , 2004, Neuroreport.

[19]  X. Ou,et al.  Dual Functions of Transcription Factors, Transforming Growth Factor-β-inducible Early Gene (TIEG)2 and Sp3, Are Mediated by CACCC Element and Sp1 Sites of Human Monoamine Oxidase (MAO) B Gene* , 2004, Journal of Biological Chemistry.

[20]  L. Miller,et al.  An mSin3A interaction domain links the transcriptional activity of KLF11 with its role in growth regulation , 2003, The EMBO journal.

[21]  A. Parini,et al.  Age-dependent increase in hydrogen peroxide production by cardiac monoamine oxidase A in rats. , 2003, American journal of physiology. Heart and circulatory physiology.

[22]  Franklyn G. Prendergast,et al.  A Conserved α-Helical Motif Mediates the Interaction of Sp1-Like Transcriptional Repressors with the Corepressor mSin3A , 2001, Molecular and Cellular Biology.

[23]  R. Urrutia,et al.  Molecular Cloning and Characterization of TIEG2Reveals a New Subfamily of Transforming Growth Factor-β-inducible Sp1-like Zinc Finger-encoding Genes Involved in the Regulation of Cell Growth* , 1998, The Journal of Biological Chemistry.

[24]  G. Gores,et al.  Overexpression of the TGFbeta-regulated zinc finger encoding gene, TIEG, induces apoptosis in pancreatic epithelial cells. , 1997, The Journal of clinical investigation.

[25]  Alan Frazer,et al.  Pharmacology of antidepressants. , 1997, Journal of clinical psychopharmacology.

[26]  T. Kelly,et al.  Validity of DSM‐III‐R diagnosis by psychological autopsy: a comparison with clinician ante‐mortem diagnosis , 1996, Acta psychiatrica Scandinavica.

[27]  P. Seeburg,et al.  cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[28]  T. McMahon,et al.  Acute Functional Tolerance to Ethanol Mediated by Protein Kinase Cɛ , 2007, Neuropsychopharmacology.

[29]  J. Shih,et al.  Monoamine oxidase: from genes to behavior. , 1999, Annual review of neuroscience.

[30]  B. Winblad,et al.  Biogenic amines in human brain in normal aging, senile dementia, and chronic alcoholism. , 1980, Advances in biochemical psychopharmacology.