Faculty Bibliography

BACKGROUND:Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects spinal cord and cortical motor neurons. An increasing amount of evidence suggests that mitochondrial dysfunction contributes to motor neuron death in ALS. Peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) is a principal regulator of mitochondrial biogenesis and oxidative metabolism. RESULTS:In this study, we examined whether PGC-1α plays a protective role in ALS by using a double transgenic mouse model where PGC-1α is over-expressed in an SOD1 transgenic mouse (TgSOD1-G93A/PGC-1α). Our results indicate that PGC-1α significantly improves motor function and survival of SOD1-G93A mice. The behavioral improvements were accompanied by reduced blood glucose level and by protection of motor neuron loss, restoration of mitochondrial electron transport chain activities and inhibition of stress signaling in the spinal cord. CONCLUSION/CONCLUSIONS:Our results demonstrate that PGC-1α plays a beneficial role in a mouse model of ALS, suggesting that PGC-1α may be a potential therapeutic target for ALS therapy.

Hormones, including estrogen and progesterone, and their receptors play an important role in the development and progression of ovarian carcinoma. Androgen, its receptor and coactivators have also been implicated in these processes. p44/Mep50/WDR77 was identified as a subunit of the methylosome complex and lately characterized as a steroid receptor coactivator that enhances androgen receptor as well as estrogen receptor-mediated transcriptional activity in a ligand-dependent manner. We previously described distinct expression and function of p44 in prostate, testis, and breast cancers. In this report, we examined the expression and function of p44 in ovarian cancer. In contrast to findings in prostate and testicular cancer and similar to breast cancer, p44 shows strong cytoplasmic localization in morphologically normal ovarian surface and fallopian tube epithelia, while nuclear p44 is observed in invasive ovarian carcinoma. We observed that p44 can serve as a coactivator of both androgen receptor (AR) and estrogen receptor (ER) in ovarian cells. Further, overexpression of nuclear-localized p44 stimulates proliferation and invasion in ovarian cancer cells in the presence of estrogen or androgen. These findings strongly suggest that p44 plays a role in mediating the effects of hormones during ovarian tumorigenesis

BACE1 (β-secretase) plays a central role in the β-amyloidogenesis of Alzheimer's disease (AD). The ubiquitin-proteasome system, a major intracellular protein quality control system, has been implicated recently in BACE1 metabolism. We report that the SCF(Fbx2) -E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. Physiologically, we found that Fbx2 was expressed in various intracellular organelles in brain neurons and that BACE1 is colocalized with Fbx2 and the amyloid precursor protein (APP), mainly at the early endosome and endoplasmic reticulum. The former are believed to be the major intracellular compartments where the APP is cleaved by BACE1 and β-amyloid is produced. Importantly, we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced β-amyloid production. In the search for specific endogenous modulators of Fbx2 expression, we found that PPARγ coactivator-1α (PGC-1α) was capable of promoting the degradation of BACE1 through a mechanism involving Fbx2 gene expression. Interestingly, we found that the expression of both Fbx2 and PGC-1α was significantly decreased in the brains of aging Tg2576 mice. Our in vivo studies using a mouse model of AD revealed that exogenous adenoviral Fbx2 expression in the brain significantly decreased BACE1 protein levels and activity, coincidentally reducing β-amyloid levels and rescuing synaptic deficits. Our study is the first to suggest that promoting Fbx2 in the brain may represent a novel strategy for the treatment of AD.

While epidermal growth factor receptor (EGFR) dysregulation is known to play a critical role in prostate carcinogenesis, there has been no direct evidence indicating EGFR mutations induce tumorigenesis in prostate cancer. We previously identified four novel EGFR somatic mutations in the EGFR tyrosine kinase domain of prostate cancer patients: G735S, G796S, E804G and R841K. In this study, we investigated the oncogenic potential of these somatic mutations by establishing stable clonal NIH3T3 cells expressing these four mutations and WT EGFR to determine their ability to increase cell proliferation and invasion. In the absence of the EGF ligand, cell proliferation was readily increased in G735S, G796S and E804G mutants compared to WT EGFR. The addition of EGF ligand greatly increased cell growth and transforming ability of these same EGFR mutants. Matrigel invasion assays showed enhanced invasion with G735S, G796S and E804G mutants. Western blot analysis showed that these EGFR mutations enhanced cell growth and invasion via constitutive and hyperactive tyrosine phosphorylation and led to the activation of mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3) and Akt pathways. Our findings demonstrate the oncogenic activation of three novel EGFR somatic missense mutations in prostate cancer. Molecules that regulate the mechanisms of their oncogenic activation represent novel targets for limiting tumor cell progression, and further elucidation of these mutations will have utility in prostate cancer treatment.Oncogene advance online publication, 14 January 2008; doi:10.1038/sj.onc.1210983

Bovine seminal plasma contains a group of similar proteins, namely BSP-A1, BSP-A2, BSP-A3, and BSP-30-kDa (collectively called BSP proteins), and they are secreted by the seminal vesicles. In our study, we purified the BSP-A1/-A2 through affinity chromatography and found for the first time that BSP-A1/-A2 can inhibit the activity of protein kinase C (PKC) and tyrosine protein kinase (TPK). The inhibition was dose dependent. When the PKC and TPK activities are expressed as the logarithm of percentage activity taking the activity in the absence of the BSP-A1/-A2 as 100%, there is a linear relationship between the their activities and the dose of BSP-A1/-A2.