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Characterizing the function of extracellular protein kinase A in angiogenesis and the effects of Zfp68 and pharmacological inhibitors in adipogenesis

Szkudlarek, Maria

Abstract Details

2010, Doctor of Philosophy in Biomedical Sciences (Ph.D.), University of Toledo, College of Medicine.

Cyclic AMP (cAMP) is a ubiquitous intracellular second messenger whose major intracellular function in eukaryotes is the activation of protein kinase A (PKA). PKA, a well known member of the serine-threonine protein kinase superfamily, is implicated in the control of a variety of cellular processes. While the role of intracellular PKA holoenzyme in cell growth has been widely investigated, little is known about the presence of PKA activity in the extracellular surface of cells. Here we show, using the in utero chicken embryo chorioallantoic membrane assay, that the extracellular form of PKA (ECPKA), from conditioned media of cultured cancer cells, inhibits angiogenesis. Whether the aberrant release of ECPKA is just a bystander effect or might have an important function in cancer development warrant further investigation and so does the potential application as a biomarker in cancer.

Obesity, a multifactorial and chronic disorder has risen to alarming levels. The World Health Organization has estimated that worldwide over one billion adults are overweight, including at least 300 million of them being obese. Obese patients are at a higher risk of hypertension and increased risk of cardiovascular disease, dyslipidemia, osteoarthritis, and diabetes. Obesity treatment has become a major public health concern and burden on the health care system. Current pharmacotherapeutic options for treating obesity and related metabolic disorders remain very limited and ineffective. The development of more effective drugs has become a priority. Here we present two agents with anti-adipogenic activity: prieurianin and salinomycin. Prieurianin, a limonoid, causes weight loss by reducing energy intake in morbidly obese mice and in mice on high-calorie diet. Prieurianin is also anti-adipogenic by inhibiting the proliferation and differentiation of preadipocytes into adipocytes, and induces either dedifferentiation or delipidation of mature adipocytes. Microarray analysis revealed number of gene expression changes following treatment with prieurianin, including a number of genes involved in fat metabolism. However, we focused our attention in the subset of early response genes, among which, we found previously identified transcriptional repressor zinc finger protein 68 (Zfp68). Salinomycin is a coccidiostat and antibacterial agent that belongs to a family of a polyether ionophore antibiotics. Here, we show that salinomycin inhibits the differentiation of preadipocytes into adipocytes and is a potent inhibitor of transcriptional activity of major adipogenic transcription factors. These results suggest that ionophore antibiotics or their derivatives could be further exploited as novel anti-obesity therapies and as pharmacological probes for the study of adipose biology.

Khew-Voon Chin, Ph.D. (Committee Chair)
Sonia Najjar, Ph.D. (Committee Member)
Ivana de la Serna, Ph.D. (Committee Member)
Sandrine Pierre, Ph.D. (Committee Member)
Randall Worth, Ph.D. (Committee Member)
138 p.

Recommended Citations

Citations

  • Szkudlarek, M. (2010). Characterizing the function of extracellular protein kinase A in angiogenesis and the effects of Zfp68 and pharmacological inhibitors in adipogenesis [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1270565982

    APA Style (7th edition)

  • Szkudlarek, Maria. Characterizing the function of extracellular protein kinase A in angiogenesis and the effects of Zfp68 and pharmacological inhibitors in adipogenesis. 2010. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1270565982.

    MLA Style (8th edition)

  • Szkudlarek, Maria. "Characterizing the function of extracellular protein kinase A in angiogenesis and the effects of Zfp68 and pharmacological inhibitors in adipogenesis." Doctoral dissertation, University of Toledo, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=mco1270565982

    Chicago Manual of Style (17th edition)