Research Article: A filtering strategy identifies FOXQ1 as a potential effector of lamin A dysfunction

Date Published: August 31, 2012

Publisher: Impact Journals LLC

Author(s): Jose Candelario, Leng-Ying Chen, Paul Marjoram, Sita Reddy, Lucio Comai.



Small increases in the expression of wild-type prelamin A are sufficient to recapitulate the reduced cell proliferation and altered nuclear membrane morphology observed in cells expressing progerin, the mutant lamin A associated with progeria. We hypothesized that the manifestation of these phenotypes in cells expressing elevated levels of wild-type prelamin A or progerin is caused by the same molecular effectors, which play a central role in the onset of the progeroid phenotype. To experimentally test this hypothesis, we compared the transcriptomes of isogenic diploid fibroblasts expressing progerin or elevated levels of wild-type prelamin A with that of wild-type fibroblasts. We subsequently used the reversion towards normal of two phenotypes, reduced cell growth and dismorphic nuclei, by treatment with farnesyltransferase inhibitor (FTI) or overexpression of ZMPSTE24, as a filtering strategy to identify genes linked to the onset of these two phenotypes. Through this analysis we identified the gene encoding for the transcription factor FOXQ1, as a gene whose expression is induced in both cells expressing progerin and elevated levels of wild-type prelamin A, and subsequently reduced in both cell types upon conditions that ameliorate the phenotypes. We overexpressed FOXQ1 in normal fibroblasts and demonstrated that increased levels of this factor lead to the development of both features that were used in the filtering strategy. These findings suggest a potential link between this transcription factor and cell dysfunction induced by altered prelamin A metabolism.

Partial Text

Lamin A is a component of the nuclear lamina that is synthesized as a prelamin A precursor that then undergoes several sequential post-translational modifications to generate mature lamin A. Mutations in the lamin A/C gene are associated with a variety of disorders, collectively termed laminopathies [1], among which is the progeroid disease Hutchinson-Gilford Progeria Syndrome (HGPS) [2]. HGPS (progeria) and Werner syndrome, also known as adult progeria, are genetic diseases that may provide insights on the mechanisms of normal human aging [3, 4]. The majority of cases of HGPS are caused by a point mutation in the lamin A/C gene that lead to the production of a permanently farnesylated mutant lamin A protein termed progerin [5, 6]. The production of progerin leads to the progressive appearance of several cellular alterations that cause the onset of an accelerated aging phenotype. Progeria cells and HeLa cells expressing ectopic progerin display growth defects and altered nuclear membrane morphology. Both cellular phenotypes can be improved by inhibition of farnesylation by treatment with farnesyl transferase inhibitors (FTIs) [7-11]. More recently, several studies have demonstrated that treatment with rapamycin, an inhibitor of the growth-promoting mTOR signaling pathway and potential drug for anti-aging therapy [12], limits the accumulation of progerin, improves the cellular phenotype of progerin-expressing cells and rescue tissue functions in lamins deficient mice [13-16]. These findings suggest that mammalian target of rapamycin (mTOR) inhibitors could be of therapeutic value for progeria and possibly other laminopathies [17].

The poor proliferation of fibroblasts expressing progerin is the result of both premature senescence and apoptosis [11], two key features of cells expressing progerin or elevated levels of prelamin A that are likely to contribute to the premature aging phenotype of HGPS. How accumulation of progerin or partially processed prelamin A results in the premature onset of cell dysfunction is unknown but likely linked to alterations in fundamental nuclear processes.





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