Keywords

Apoptosis, Cell cycle, Cell death, DNA binding proteins, Heart -- Diseases, Melanoma, Nuclear proteins, Repressors, Genetic, Transcription factors

Abstract

Omi/HtrA2 is a mitochondrial serine protease that is known to translocate to the cytoplasm upon induction of apoptosis and to activate caspase-dependent and caspase-independent cell death. The molecular mechanism of Omi/HtrA2's function is not clear but involves degradation of specific substrates. These substrates include cytoplasmic, mitochondrial, as well as nuclear proteins. We have isolated a new Omi/HtrA2 interactor, the THAP5 protein. THAP5 is a fifth member of a large family of transcription factors that are involved in cell proliferation, apoptosis, cell cycle control, chromosome segregation, chromatin modification and transcriptional regulation. THAP5 is an approximately 50kDa nuclear protein, with a restricted pattern of expression. Furthermore, there is no mouse or rat homolog for this protein. THAP5 mRNA is highly expressed in the human heart but some expression is also seen in the brain and skeletal muscle. The normal function of THAP5 in the heart or heart disease is unknown. THAP5 protein level is significantly reduced in the myocardial infarction (MI) area in the heart of patients with coronary artery disease (CAD). This part of the heart sustains most of the cellular damage and apoptosis. Our data clearly show that THAP5 is a specific substrate of the proapoptotic Omi/HtrA2 protease and is cleaved and removed during cell death. The molecular mechanism of THAP5's function is unclear. THAP5 can bind to a specific DNA sequence and repress transcription of a reporter gene. Our work suggests that THAP5 is a tissue specific transcriptional repressor that plays an important role in the normal function of the human heart as well as in the development of heart disease.

Notes

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Graduation Date

2010

Semester

Fall

Advisor

Zervos, Antonis S.

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Format

application/pdf

Identifier

CFE0003412

URL

http://purl.fcla.edu/fcla/etd/CFE0003412

Language

English

Release Date

December 2010

Length of Campus-only Access

None

Access Status

Doctoral Dissertation (Open Access)

Subjects

Dissertations, Academic -- Medicine, Medicine -- Dissertations, Academic

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