Cellular Control of Metabolism
Jürgen Berger/Max Planck Institute
Cells require tight regulation of metabolism to maintain homeostasis and viability.
Metabolism = the chemical reactions in a cell or organism
Homeostasis = control of a system keep it stable or constant
Hepatic ArteryHigh oxygen
Central VeinLow oxygen
Adapted from http://www.siumed.edu/
Cells Adapt to Their Environment to Maintain Homeostasis
O2
Control of Cholesterol and Fat Synthesis
Acetyl-CoA, NADPH, O2, ATP
Cholesterol& Fat
Cholesterol& Fat
SynthesisSREBP
SREBP Controls Synthesis of Cholesterol and Fat
Korn et al., J. Clin. Invest. 1998, 102:2050-2060.
Normal Liver High SREBP
Talk Outline
1. Yeast SREBP is controlled by oxygen
2. SREBP is required for virulence of pathogenic fungi.
3. What can this tell us about human cancer?
Control of Cholesterol and Fat Synthesis
Acetyl-CoA, NADPH, O2, ATP
Cholesterol& Fat
Cholesterol& Fat
SynthesisSREBP
X
Cryptococcus neoformans
Human opportunistic fungal pathogen
Infects ~30% of patients with AIDS in Africa and Southeast Asia
Common diseases: - meningoencephalitis - pneumonia
21%O2
14%
3%
Hypothesis: SREBP is required for growth in animals.
Cryptococcus neoformans
June Kwon-Chung – NIH, NIAID
SREBP is Required for A. fumigatus Low Oxygen Growth
Willger et al. PLoS Pathogens 2008
Wild-type
sre1D
Is SREBP a Therapeutic Target for Pancreatic Cancer?
Tumor Hypoxia (Low O2)
Cholesterol & Fat Synthesis
Tumor Growth
SREBP
Is the SREBP Pathway a Therapeutic Target for Pancreatic Cancer?
Tumor Hypoxia (low O2)
Cholesterol & Fat Synthesis
Tumor Growth
SREBP
Drugs
- Yeast SREBP is controlled by oxygen and required for fungal pathogenesis.
- SREBP may be required for pancreatic tumor growth and a new therapeutic target for this devastating disease.
- Studies of a simple yeast can provide important insights into human disease.
Summary