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Submitted on October 11, 2004
Accepted on January 18, 2005
GSU-driven Pituitary Tumor Transforming Gene (PTTG) Transgenic Mice
Departments of Medicine and S. Mark Taper Imaging Center, Cedars Sinai Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90048
* To whom correspondence should be addressed. E-mail: melmeds{at}cshs.org.
Pituitary tumor transforming gene (PTTG), a securin protein isolated from pituitary tumor cell lines, is highly expressed in invasive tumors and exhibits characteristics of a transforming gene. To determine the role of PTTG in pituitary tumorigenesis, transgenic human PTTG1 was targeted to the mouse pituitary using the 
-subunit of glycoprotein hormone (GSU) promoter. Males showed plurihormonal focal pituitary transgene expression with Luteinizing Hormone (LH)-, Thyroid Stimulating Hormone (thyrotropin)- and unexpectedly also Growth Hormone (GH)-cell focal hyperplasia and adenoma, associated with increased serum LH, GH, testosterone, and/or IGF-I levels. Magnetic Resonance Imaging (MRI) revealed both pituitary and prostate enlargement at 9-12 months. Urinary obstruction caused by prostatic hyperplasia, seminal vesicle hyperplasia, with renal tract inflammation, resulted in death by 10 months in some animals. Pituitary PTTG expression results in plurihormonal hyperplasia and hormone-secreting microadenomas with profound peripheral growth stimulatory effects on the prostate and urinary tract. These results provide evidence for early pituitary plasticity, whereby PTTG over-expression results in a phenotype switch in early pituitary stem cells, and promotes differentiated polyhormonal cell focal expansion.
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