David L. Teply

By Elena D. Bazhanova and David L. Teply

This study reveals the molecular regulation mechanisms of neurosecretory cell apoptosis in physiological and pathological (oncogene human epidermal growth factor receptor (HER)-2/Neu overexpression) aging. As we have shown previously, apoptosis level in hypothalamic neurosecretory centers increases in aging, and a low level of apoptosis in aged HER-2/Neu transgenic mice is associated with p53-dependent cascade suppression. In this chapter, we consider the participation of p53-regulating genes and p53 target genes in activation of this cascade during physiological aging, as well as suppression under HER-2/Neu overexpression. However, cell resistance to apoptosis may also be due to the activity of cytokine-dependent STAT-signaling pathway, including the high expression of survivin belonging to the family of inhibitors of apoptosis proteins (IAP). Also, another cytokine-dependent signaling, an extrinsic apoptosis pathway associated with the family of tumor necrosis factor (TNF) receptors, has been investigated. Thus, in the present work, three signaling cascades are considered: p53-dependent (the expression and interaction of apoptosis-associated proteins p53, WRN, pin1, p21, and caspase-3), STAT-mediated (STAT1, 3, 5, 6, and survivin), and TNF-dependent (CD95 (FAS), Fas-associated death domain (FADD), TNF receptor–associated death domain (TRADD), and caspase-8). These cascades are involved in both the activation of apoptosis and its suppression. This will reveal the general trends of regulation of neurosecretory cell apoptosis during aging.

Part of the book: Hypothalamus in Health and Diseases