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Job Title
Research Assistant II
Academic Rank
Staff/Research Assistant
Department
Medicine
Authors
Pieter Cory, Dean M. Rosenthal, Damir Khabibullin, Michel Alchoueiry, Eli Akl, Heng-Jia Liu, Yan Tang, Julia F. Charles, Volkhard Lindner, Nicola Alesi, Elizabeth P. Henske
Principal Investigator
Elizabeth Henske
Categories
Tags
Tuberous Sclerosis Complex (TSC) is a hereditary syndrome caused by mutational inactivation of TSC1 or TSC2 tumor suppressor genes, causing hyperactivation of the kinase mTORC1.
Collagen-Triple-Helix-Repeat (CTHRC1) is a secreted glycoprotein that is highly expressed in many cancers and associated with poor prognosis.
CTHRC1 mRNA expression is elevated in cellular and murine models of TSC, ranging from 6-60-fold compared to controls. Furthermore, Cthrc1 mRNA is elevated in cystic kidney tissue from a TSC mouse model. CTHRC1 knockdown in TSC2-/- cells decreased proliferation (~2.5-fold, P < 0.0001) and colony formation (~7-fold, P < 0.0001) with no effect on TSC2+/+ cells.
Pharmacological and genetic inhibition of mTORC1 did not decrease CTHRC1 mRNA or protein, indicating that the upregulation of CHTRC1 in TSC is mTORC1-independent.
The transcription factors TFEB and TFE3 are hyperactive in TSC. CTHRC1 mRNA and protein expression are decreased by TFEB/TFE3 knockdown in TSC1-/- mouse (~2-fold, p < 0.0001) and human cells (~2.5-fold, p < 0.01).
Our results indicate in TSC, that CTHRC1 expression is driven by TFEB/TFE3, and promotes tumor cell proliferation. CTHRC1 expression is insensitive to mTORC1 inhibition, suggesting an important role for CTHRC1 in the pathogenesis and therapy of TSC.
Tuberous Sclerosis Complex (TSC) is a hereditary syndrome caused by mutational inactivation of TSC1 or TSC2 tumor suppressor genes, resulting in hyperactivation of a protein called mTORC1.
This project is focused on another protein, CTHRC1, that has never been studied in TSC. CTHRC1 is linked to cellular growth in other diseases, where it is associated with poor clinical prognosis.
We have discovered that CTHRC1 protein and mRNA levels are elevated in cells that lack the TSC proteins. CTHRC1 is elevated 15-fold in TSC1-deficient cells vs. controls, and in TSC2-deficient cells, CTHRC1 is elevated 100-fold. Interestingly, these high levels of CTHRC1 are not suppressed by the mTORC1 inhibitor Rapamycin. Levels of CTHRC1 are also increased in human angiomyolipoma and in kidneys from mice with TSC.
In TSC2-deficient cells, CTHRC1 is a major determinant of cellular growth. If we inhibit CTHRC1, the growth of the cells decreases ~2.5-fold on plastic dishes and ~3.5-fold in a three-dimensional assay called “colony formation.”
These data suggest CTHRC1 is an important driver of tumor cell growth in TSC. Because CTHRC1 expression is not affected by the Rapamycin, the protein could help explain why tumors in TSC are not eliminated by therapy with mTORC1 inhibitors.
