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The pituitary is a small endocrine gland that controls vital homeostatic functions. It is called the "master gland" because it directs other organs and endocrine glands, such as the thyroid, adrenals, and liver, to suppress or induce hormone production. Under control of growth factors and transcription factors, pituitary progenitor cells differentiate into five types of hormone secreting cells, including lactotroph (prolactin secreting), somatotroph (GH secreting), gonadotroph (FSH and LH secreting), thyrotroph (TSH secreting) and corticotroph (ACTH secreting).
Pituitary tumorigenesis and novel treatment approaches to pituitary disease
Anat Ben-Shlomo, MD is studying regulatory factors involved in pituitary tumorigenesis and progression, and novel treatment approaches to pituitary disease, especially somatostatin receptors and their novel ligands. She was the first to present evidence to support the existence of ligand-independent constitutive somatostatin receptor activity in vitro, regulating adrenocorticotropin secretion, corticotroph cell response to stress and somatotroph growth hormone synthesis.
Cell cycle control in pituitary tumors
Vera Chesnokova, PhD is investigating the role of cell cycle control in pituitary tumors. PTTG initiates pituitary tumor formation; however, pituitary tumors grow slowly and almost never progress to malignancy. We found that PTTG, while triggering pituitary tumor growth, also promotes mechanisms restraining pituitary tumor cell proliferation. Thus, in GH-secreting pituitary adenomas, CDK inhibitors play an important role in pituitary tumor cell proliferation arrest, evidenced by high levels of senescence-associated β-galactosidase (Figure 1).
In nonfunctioning pituitary adenomas (gonadotroph cell adenomas), tumor growth is restrained by activation of tumor suppressor p15 (Figure 2). Thus, lineage-specific trophic factors determine pituitary tumor cell proliferation rates. We continue to study effects of proliferation arrest on tumor cell hormone producing functions.
Fig. 1 Confocal image of double fluorescence immunohistochemistry of p21 (green) and senescence-associated β-galactosidase (red) proteins co-expression in human pituitary adenomatous but not in normal adjacent tissue. Right panel-high resolution (x63) image of the same slide.
Fig. 2 Confocal image of non-tumorous pituitary tissue and non-functioning pituitary adenoma (NFA) specimens. NFA abundantly express clusterin (green, cytoplasmic) and p15 (green) . Insert: high resolution (x63) of the same slide showing intranuclear localization of p15.
Pituitary progenitor cells
Fig. 3 Hypothalamus-pituitary-liver axis.
Yunguang Tong, PhD is studying how pituitary progenitor cells differentiate into somatotroph cells but not into other hormone secreting cells. Understanding the underlying mechanisms will help regenerate somatotroph cells to treat GH-deficient patients.
To guide pituitary research and develop new treatments for pituitary diseases, we are using an integrative genomics approach to develop a pituitary biomarker database for storing information of high-throughput studies, analyses and detected biomarkers.
- Gene expression microarray to determine differentially expressed genes in pituitary disorders
- SNP /CGH microarray to determine the contribution of copy number variation to pituitary tumor development
- Whole exome sequencing to determine the contribution of somatic mutation to pituitary tumor development (Figure 3)
Molecular pathogenesis and treatment for pituitary adenomas
Cuiqi Zhou, PhD, is studying molecular pathogenesis and treatment for pituitary adenomas, utilizing molecular, cellular and animal models. She especially focuses on studying regulatory mechanisms and functions of pituitary tumor transforming gene (PTTG), and hormone regulation in pituitary tumors. PTTG is abundantly expressed in multiple human tumors, including pituitary tumors, and correlates with tumor invasiveness, metastasis and angiogenesis. Proximal regulatory mechanisms for tumor PTTG abundance remain unclear. Zhou has systematically investigated PTTG regulatory mechanisms, which are typically mediated by cell cycle regulator Rb/E2F1, by STAT3 and by a universal transcription factor Oct-1. These findings extend our knowledge of tumor PTTG abundance and support future anti-tumor therapeutic approaches.
Vertebrate hypothalamic-pituitary system
Ning-Ai Liu, MD, PhD, uses zebrafish to investigate development and function of the vertebrate hypothalamic-pituitary system and to discover new therapeutic strategies to combat pituitary disorders. Zebrafish have emerged as a viable model organism for bioactive small molecule discovery. The zebrafish and mammalian genetic and tissue/organ makeup are similar. Thus, small molecules discovered in zebrafish screens often have analogous effects in mammalian systems. In particular, using established zebrafish models of human pituitary disease, it is now possible to assess the specificity, efficacy, and toxicity of small molecules in the context of live organisms (Figure 4).
Fig. 4 Transgenic zebrafish embryo with GFP and RFP expression specifically targeted to corticotrophs (green) and lactotrophs (red) respectively.
In vivo time-lapse imaging of embryonic pituitary lactotroph (red) and corticotroph (green) ontogeny in germline transgenic zebrafish at 18 – 26 hours post fertilization.