Search

Zhou, Yun-Ping, John C. Pena, Michael W. Roe, Anshu Mittal, Matteo Levisetti, Aaron C. Baldwin, William Pugh, Diane Ostrega, Noreen Ahmed, Vytautas P. Bindokas, Louis H. Philipson, Douglas Hanahan, Craig B. Thompson, and Kenneth S. Polonsky. Overexpression of Bcl-[x.sub.L] in [Beta]-cells prevents cell death but impairs mitochondrial signal for insulin secretion. Am. J. Physiol. Endocrinol. Metab. 278: E340--E351, 2000.--To study effects of Bcl-[x.sub.L] in the pancreatic [Beta]-cell, two transgenic lines were produced using different forms of the rat insulin promoter. Bcl-[x.sub.L] expression in [Beta]-cells was increased 2- to 3-fold in founder (Fd) 1 and over 10-fold in Fd 2 compared with littermate controls. After exposure to thapsigargin (10 [micro]M for 48 h), losses of cell viability in islets of Fd 1 and Fd 2 Bcl-[x.sub.L] transgenic mice were significantly lower than in islets of wild-type mice. Unexpectedly, severe glucose intolerance was observed in Fd 2 but not Fd 1 Bcl-[x.sub.L] mice. Pancreatic insulin content and islet morphology were not different from control in either transgenic line. However, Fd 2 Bcl-[x.sub.L] islets had impaired insulin secretory and intracellular free [Ca.sup.2+] ([[[Ca.sup.2+]].sub.i]) responses to glucose and KCL. Furthermore, insulin and [[[Ca.sup.2+]].sub.i] responses to pyruvate methyl ester (PME) were similarly reduced as glucose in Fd 2 Bcl-[x.sub.L] islets. Consistent with a mitochondrial defect, glucose oxidation, but not glycolysis, was significantly lower in Fd 2 Bcl-[x.sub.L] islets than in wild-type islets. Glucose-, PME-, and [Alpha]-ketoisocaproate-induced hyperpolarization of mitochondrial membrane potential, NAD(P)H, and ATP production were also significantly reduced in Fd 2 Bcl-[x.sub.L] islets. Thus, although Bcl-[x.sub.L] promotes [Beta]-cell survival, high levels of expression of Bcl-[x.sub.L] result in reduced glucose-induced insulin secretion and hyperglycemia due to a defect in mitochondrial nutrient metabolism and signaling for insulin secretion. apoptosis; calcium; islets of Langerhans; mitochondria

Studies the effects of Bcl-XL in the pancreatic beta cell by producing two cell lines using different forms of the rat insulin promoter. Observation of glucose intolerance; Reduction in glucose-induced insulin secretion and hyperglycemia due to overexpression of Bcl-XL and defect in mitochondrial nutrient metabolism.

Transgenic mice that overexpress the anti-apoptotic gene bcl-xL under the control of the keratin 14 promoter have significantly shorter hair than non-transgenic littermates. The deficit in hair length correlated with a decrease in the duration of anagen, the growth phase of the hair cycle. A prolongation in telogen, the resting phase of the hair cycle, was also observed in adult animals. In the developing hair bulb, bcl-xL transgene expression was observed exclusively in the outer root sheath (ORS) cells. Bcl-xL expression enhanced the survival of ORS cells treated with apoptotic stimuli. The results suggest that preventing the apoptotic death of ORS cells during anagen leads to a more rapid termination of progenitor cell commitment/proliferation, while the increased survival of ORS cells during telogen delays the initiation of a new hair cycle. ORS cells produce fibroblast growth factor-5 (FGF-5), which acts in a paracrine fashion to terminate precursor cell division during anagen. The short hair phenotype of bcl-xL transgenic mice was substantially reversed in FGF-5-deficient mice. Thus, the production of growth inhibitory factors by ORS cells may provide a mechanism through which the hair-growth cycle is regulated by cell survival. [ABSTRACT FROM AUTHOR]