Keynote Conference - Interevent

L#15
Emerging roles of mitotic centrosomes in asymmetric events
and cilia disorders
Stephen Doxey
University of Massachusetts Medical School , Department
Program in Molecular Medicine University of Massachusetts
Medical School 373 Plantation Street Worcester MA 01605
Mitosis is a fundamental process required for cell proliferation
in all multicellular organisms. Much has been learned about
the underpinnings of this process over the last century, but
new and unexpected insights continue to be uncovered. Here
we describe two novel and unanticipated findings associated
with mitosis. The first is the unexpected identification of
mitotic functions for proteins long known to function in cilia
formation and ciliopathies. We show that the cilia proteins
IFT88, IFT20 and IFT57 play a crucial role in the organization of
spindle poles. Their depletion disrupts astral microtubules and
misorients spindles. This has important implications for
cystogenesis that accompanies ciliopathies. A second study
shows that the midbody, a singular organelle formed between
dividing daughter cells, is inherited by one daughter cell rather
than being lost as a remnant or residual body as previously
believed. Midbodies are inherited asymmetrically by the
daughter cell with the older centrosome. Disruption of the
older centrosome randomizes midbody inheritance. Midbodies
accumulate in stem cells and cancer ‘stem cells’ but not in
normal or differentiating cells. In differentiating cells midbodies
are degraded by receptor-mediated autophagy; stem cells and
cancer stem cells evade autophagic degradation. Midbody
enrichment by blocking degradation enhances reprogramming
to induced pluripotent stem cells and increases in vitro
tumorigenicity of cancer cells. These results reveal unexpected
post-mitotic roles for midbodies in stem cells and cancer ‘stem
cells’.
L#16
Growth hormone and aging; benefits of endocrine defects
Andrzej Bartke
Department of Internal Medicine, Southern Illinois University
School of Medicine, Springfield, Illinois, USA
Growth hormone (GH) levels progressively decline after reaching
maximal levels in early adulthood and it was suspected that this
decline may represent one of the causes of aging. Surprisingly,
mice with mutations that cause GH deficiency and mice with
targeted deletion of GH receptors live much longer than their
normal siblings and exhibit symptoms of delayed aging.
Extended longevity of these mutants is associated with reduced
growth and adult body size, improved maintenance of
pluripotent bone marrow stem cells, reduced incidence of
cancer, increased fibroblast resistance to various cytotoxic
stressors and various metabolic changes. Circulating levels of
insulin and glucose are reduced and insulin sensitivity measured
by insulin tolerance tests is enhanced. In GH receptor deleted
(GHRKO) mice improved whole animal insulin sensitivity has
been related to increased levels and phosphorylation of hepatic
insulin receptors and reduced inhibitory (Serine 307)
phosphorylation of IRS-1. mTOR signaling likely contributes to
this change in IRS-1 phosphorylation. Results of surgical
removal of intraabdominal adipose tissue indicate that
adiponectin secreted by these fat depots enhances insulin
sensitivity of long-lived GH-related mutants. Metabolic shifts in
GH-deficient and GH-resistant mice also include increased
oxygen consumption and reduced respiratory quotient, implying
increased reliance on lipids as metabolic fuel. In sum,
suppression of GH signals slows aging in mice by multiple
mechanisms. Supported by NIA.
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