Browsing by Author "Campbell, Amanda M."

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    Phosphatase of regenerating liver 2 (PRL2) deficiency impairs Kit signaling and spermatogenesis
    (ASBMB, 2014-02-07) Dong, Yuanshu; Zhang, Lujuan; Bai, Yunpeng; Zhou, Hong-Ming; Campbell, Amanda M.; Chen, Hanying; Yong, Weidong; Zhang, Wenjun; Zeng, Qi; Shou, Weinian; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of Medicine
    The Phosphatase of Regenerating Liver (PRL) proteins promote cell signaling and are oncogenic when overexpressed. However, our understanding of PRL function came primarily from studies with cultured cell lines aberrantly or ectopically expressing PRLs. To define the physiological roles of the PRLs, we generated PRL2 knock-out mice to study the effects of PRL deletion in a genetically controlled, organismal model. PRL2-deficient male mice exhibit testicular hypotrophy and impaired spermatogenesis, leading to decreased reproductive capacity. Mechanistically, PRL2 deficiency results in elevated PTEN level in the testis, which attenuates the Kit-PI3K-Akt pathway, resulting in increased germ cell apoptosis. Conversely, increased PRL2 expression in GC-1 cells reduces PTEN level and promotes Akt activation. Our analyses of PRL2-deficient animals suggest that PRL2 is required for spermatogenesis during testis development. The study also reveals that PRL2 promotes Kit-mediated PI3K/Akt signaling by reducing the level of PTEN that normally antagonizes the pathway. Given the strong cancer susceptibility to subtle variations in PTEN level, the ability of PRL2 to repress PTEN expression qualifies it as an oncogene and a novel target for developing anti-cancer agents.
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    Phosphatase of regenerating liver: a novel target for cancer therapy
    (Taylor & Francis, 2014-05) Campbell, Amanda M.; Zhang, Zhong-Yin; Biochemistry & Molecular Biology, School of Medicine
    INTRODUCTION: Phosphatases of regenerating livers (PRLs) are novel oncogenes that interact with many well-established cell signaling pathways that are misregulated in cancer, and are known to drive cancer metastasis when overexpressed. AREAS COVERED: This review covers basic information of the discovery and characteristics of the PRL family. We also report findings on the role of PRL in cancer, cell functions and cell signaling. Furthermore, PRL's suitability as a novel drug target is discussed along with current methods being developed to facilitate PRL inhibition. EXPERT OPINION: PRLs show great potential as novel drug targets for anticancer therapeutics. Studies indicate that PRL can perturb major cancer pathways such as Src/ERK1/2 and PTEN/PI3K/Akt. Upregulation of PRLs has also been shown to drive cancer metastasis. However, in order to fully realize its therapeutic potential, a deeper understanding of the function of PRL in normal tissue and in cancer must be obtained. Novel and integrated biochemical, chemical, biological, and genetic approaches will be needed to identify PRL substrate(s) and to provide proof-of-concept data on the druggability of the PRL phosphatases.