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東京大学医科学研究所
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開催日時:平成19年3月28日(水) 10:30~12:00

開催場所:東京大学医科学研究所1号館2階会議室

講 師:Dr. David J. Kwiatkowski

所 属:Professor of Medicine&s_comma; Brigham and Women’s Hospital and Harvard
Medical School

演  題:Tuberous sclerosis: a unique tumor suppressor gene syndrome whose
genes have a critical role in cortical development

概  要:Tuberous sclerosis (TSC) is an autosomal dominant tumor suppressor
gene syndrome that leads to benign tumor development in several organs&s_comma;
including the brain&s_comma; lungs&s_comma; heart&s_comma; kidneys&s_comma; and skin&s_comma; and is due to
inactivating mutations in either of TSC1 or TSC2. Following our discovery
of the TSC1 gene a decade ago&s_comma; the TSC1 and TSC2 gene products were shown to
form a tight binding complex&s_comma; and then shown to play a critical role in an
ancestrally conserved signaling pathway to regulate the activity of the
mTORC1 complex to regulate both cell size and cell growth. Our recent
studies have focused on three aspects of TSC&s_comma; TSC1&s_comma; and TSC2.
First&s_comma; we have identified a feedback pathway that limits Akt activation
when the TSC1/TSC2 complex is inactivated. TSC1/TSC2 functions as a GTPase
activating protein (GAP) for Rheb&s_comma; which functions in its GTP-bound state to
activate the mTORC1 complex. Loss of TSC1/TSC2 leads to high levels of
Rheb-GTP and constitutive activation of mTORC1. This leads to several
different feedback effects which limit Akt activation. We identified
reduction in expression of the PDGFRs as one important mechanism of this
effect&s_comma; and have shown that it occurs at the transcriptional level. Reduced
PDGFR expression occurs whenever mTORC1 is chronically activated&s_comma; and this
effect is reversed by rapamycin treatment. The reduced PDGFR expression
also impairs signaling from EGF&s_comma; IGF&s_comma; and PMA to Akt. Over-expression of
PDGFR rescues this feedback effect and markedly enhances the tumorigenicity
of Tsc2 null fibroblasts (MEFs)&s_comma; suggesting that this feedback effect
contributes to the lack of cancer seen in TSC patients.
Second&s_comma; we have shown that rapamycin is an effective therapeutic agent
in the treatment of kidney and liver tumors that develop in TSC mouse
models. Chronic long-term (9 months) treatment with rapamycin (4mg/kg IP
3x/wk) suppresses 95% of tumor development in Tsc1+- mice. Shorter term
treatment is also very effective in causing tumor regression with conversion
of solid adenomas to residual cysts&s_comma; and reduced proliferation. In
addition&s_comma; we have recently explored the possibility that statin therapy&s_comma;
through blockade of HMG-CoA reductase&s_comma; could block isoprenylation to inhibit
G protein activity in cells lacking Tsc1/Tsc2. Atorvastatin has selective
growth effects on Tsc1/Tsc2 null MEFs&s_comma; reduces the isoprenylation and
membrane localization of Rheb&s_comma; and inhibits mTORC1 activation. Therapeutic
trials of atorvastatin in Tsc mouse models are underway.
Third&s_comma; we have developed a mouse TSC brain model. We used a SynICre
allele combined with our Tsc1c allele to induce recombination and loss of
Tsc1 during neuronal development. Tsc1c-SynICre+ mice have a median
survival of 32 days&s_comma; with tremulousness&s_comma; an enhanced startle response&s_comma; and
tendency for fatal seizures. Many cortical and hippocampal neurons are
enlarged and/or dysplastic in this Tsc1 neuronal model&s_comma; strongly express
phospho-S6&s_comma; and are ectopic in multiple sites in the cortex and hippocampus.
There is a striking delay in myelination in the mutant mice&s_comma; which appears
to be due to an inductive neuronal defect. Thus&s_comma; this model replicates
several features of human TSC brain lesions&s_comma; and implicates an important
function of Tsc1/Tsc2 in neuronal development. Finally&s_comma; rapamycin therapy
initiated at post-natal day 8 is dramatically effective in this model with
over 90% of mutant mice surviving over 100 days.
  
世話人:○服部成介、山本雅




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