The sterol 27-hydroxylase (EC 1

Hereditary inclusion body myopathy (HIBM) is a unique muscular disorder caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. GNE encodes a bi-functional enzyme acting in the biosynthetic pathway of sialic acid. Since the underlying myopathological mechanism leading to the disease phenotype is poorly understood, we have established human myoblasts cultures, derived from HIBM satellite cells carrying the homozygous M712T mutation, and identified cellular and molecular characteristics of these cells. HIBM and control myoblasts showed similar heterogeneous patterns of proliferation and differentiation. Upon apoptosis induction, phosphatidylserine externalization was similar in HIBM and controls. In contrast, the active forms of caspase-3 and -9 were strongly enhanced in most HIBM cultures compared to controls, while pAkt, downregulated in controls, remained high in HIBM cells. These results could indicate impaired apoptotic signaling in HIBM cells. Since satellite cells enable partial regeneration of the post-mitotic muscle tissue, these altered processes could contribute to the muscle mass loss seen in patients. The identification of survival defects in HIBM affected muscle cells could disclose new functions for GNE in muscle cells.

The growth-arresting properties of AG1478, unaffected by ovarian steroidal hormones, identify it as a potential lead agent for the non-surgical management of uterine leiomyomas.

No abstract

Psoriasis is characterized by hyperproliferation of keratinocytes associated with an inflammatory infiltrate in the epidermis. Among factors which may be related to hyperplasia of psoriatic keratinocytes is the persistent autocrine stimulation of the epidermal growth factor receptor (EGFR) by transforming growth factor-alpha. Owing to the pivotal role of the EGFR in driving the growth of human psoriatic keratinocytes, we examined two selective inhibitors of EGFR kinase activity: 4-(3-bromophenylamino)-6, 7-dimethoxyquinazoline (AG1517/SU5271) and 4-(3-chlorophenylamino)-6, 7-dimethoxyquinazoline (AG1478) on psoriatic keratinocytes. SU5271 potently inhibits ligand-induced autophosphorylation of EGFR, and downstream signal transduction events, including DNA replication and cell cycle progression. SU5271, at micromolar concentrations, inhibited the proliferation of keratinocytes isolated from psoriatic lesions in excellent correlation with its EGFR kinase inhibitory activity in these cells. Biologically active concentrations of SU5271 penetrated human cadaver skin, suggesting that this compound is a strong candidate as an antipsoriatic agent.