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A ubiquitin protein ligase (E3), E3Histone/LASU1 (Mule/ARF-BP1/HUWE1), was recently identified that mediates ubiquitination of core histones, the Mcl-1 anti-apoptotic protein, and the p53 tumor suppressor protein. However, the expression of E3Histone/LASU1 remains poorly studied. Because we identified E3Histone/LASU1 from the testis, we explored its regulation during spermatogenesis. In the first wave of rat spermatogenesis, E3Histone/LASU1 mRNA and protein had peak expression at days 10 and 20, respectively, and decreased with age. Consistent with these findings, immunohistochemistry revealed that E3Histone/LASU1 was highly expressed in nuclei from spermatogonia to mid-pachytene spermatocytes. There was no obvious staining in spermatids, when histones are ubiquitinated and degraded. E3Histone/LASU1 was also expressed in other tissues. However, except in neuronal cells of the brain, expression was cytoplasmic. Thus, E3Histone/LASU1 may play a role in chromatin modification in early germ cells of the testis, but also has functions in other tissues. Developmental Dynamics 236:2889-2898, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Unlabelled: We examined the effects of 60 days of co-treatment of PTH with either OPG or alendronate in oophorectomized mice. Compared with PTH alone, co-treatment of PTH with either of these two mechanistically distinct anti-catabolics improved bone volume, mechanical strength, and appendicular and axial mineralization and prolonged the beneficial effect of PTH on BMD., Introduction: Conflicting evidence exists as to whether the anabolic effect of PTH is inhibited by the action of anti-catabolics. To examine this issue, we assessed the effects of alendronate and osteoprotegerin (OPG), two anti-catabolics with different modes of action, on the anabolic activity of PTH(1-34) in the skeleton of 4-month-old oophorectomized mice., Materials and Methods: Mice treated with vehicle alone (PBS), alendronate alone (100 microg/kg/week), OPG alone (10 mg/kg twice a week), or PTH alone (80 microg/kg/day) were compared with each other and with animals administered PTH plus alendronate or PTH plus OPG. We assessed lumbar spine and femoral BMD at 0, 30, and 60 days. Contact radiography, histology, and histomorphometry, three-point bending assay of the femur, and serum osteocalcin and TRACP5b assays were performed at 2 months., Results: Although alendronate and OPG each suppressed bone turnover, at the doses used, this was more profound with OPG. Increases in lumbar spine and femoral BMD and in trabecular bone volume were at least as great with OPG as with alendronate, and mechanical indices of femoral bone strength improved only with OPG. Both produced a plateau in spine and femoral BMD increases by 30 days. Co-treatment of PTH with each anti-catabolic produced additive increases in BMD in the femur and supra-additive increases in the lumbar spine with no plateau effects. Neither anti-catabolic impeded the PTH-induced increase in bone volume or the increase in mechanical strength of the femur., Conclusions: These studies show that the highly potent anti-catabolic OPG can produce dramatic increases in BMD and bone strength; that the temporal pattern of activity of bone formation and resorption modulators may have major influence on net skeletal accrual; and that, depending on timing, inhibition of osteoclastic activity may markedly augment the anabolic action of PTH.