Transcript From Man to Yeast and Back

Measuring Cholesterol: From Man to Yeast
and Back
Peter Espenshade
Department of Cell Biology
Cellular Control of Metabolism
Cells require tight regulation of metabolism to maintain
homeostasis and viability.
Jürgen Berger/Max Planck Institute
Metabolism = the chemical reactions in a cell or organism
Homeostasis = control of a system keep it stable or constant
Cells Adapt to Their Environment to
Maintain Homeostasis
Central Vein
Low oxygen
O2
Hepatic Artery
High oxygen
Adapted from http://www.siumed.edu/
Tumor Cells Adapt to Their
Environment to Maintain Homeostasis
Semenza, 2011
Semenza, 2008
Control of Cholesterol and Fat
Synthesis
Acetyl-CoA, NADPH, O2, ATP
SREBP
Cholesterol
& Fat
Synthesis
Cholesterol
& Fat
SREBP Controls Synthesis of
Cholesterol and Fat
Normal Liver
High SREBP
Korn et al., J. Clin. Invest. 1998, 102:2050-2060.
Loss of SREBP Prevents Diabetic Fatty Liver
Moon et al. 2012 Cell Metab. 15: 240-246.
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?
Conservation of SREBP in Fungi
SREBP Responds to Oxygen in Fungi
[ O2 ]
SREBP
+O2
-O2
Gene expression required
for low oxygen growth
Control of Cholesterol and Fat
Synthesis
X
Acetyl-CoA, NADPH, O2, ATP
SREBP
Cholesterol
& Fat
Synthesis
Cholesterol
& Fat
Conservation of SREBP in Fungi
Cryptococcus neoformans
Human opportunistic fungal pathogen
Infects ~30% of patients with AIDS in Africa
and Southeast Asia
Common diseases:
- meningoencephalitis
- pneumonia
Cryptococcus neoformans
21%
O2
3%
14%
Hypothesis: SREBP is required for growth in animals.
June Kwon-Chung – NIH, NIAID
SREBP is Required for C. neoformans
Infection
7 days post-infection via tail vein
Conservation of SREBP in Fungi
SREBP is Required for A. fumigatus
Low Oxygen Growth
Wild-type
sre1D
Willger et al. PLoS Pathogens 2008
SREBP is a Conserved Virulence
Factor and Antifungal Drug Target
Tumor Cells Adapt to the Environment
to Maintain Homeostasis
Semenza, 2011
Semenza, 2008
Is SREBP a Therapeutic Target
for Pancreatic Cancer?
Tumor Hypoxia (Low O2)
SREBP
Cholesterol & Fat Synthesis
Tumor Growth
CRISPR Knockout of SREBP Pathway
Is the SREBP Pathway a Therapeutic Target
for Pancreatic Cancer?
Tumor Hypoxia (low O2)
SREBP
Drugs
Cholesterol & Fat Synthesis
Tumor Growth
Summary
- 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.
CURRENT LAB MEMBERS
Risa Burr
Sara Clasen
He Gu
Jiwon Hwang
Meredith McGuire
Sumana Raychaudhuri, PhD
Wei Shao, PhD
Shan Zhao
COLLABORATORS
espenshadelab.com
C. neoformans
June Kwon-Chung – NIH
Pancreatic cancer
FUNDING
AHN-JHU Cancer Research Fund
Anirban Maitra – SKCCC
Zeshaan Rasheed – SKCCC