Cancer Genomics

Transcriptional Regulation

Gene transcription is regulated by the complex interaction of multiple proteins that bind to DNA regulatory sequences within or near each gene. Identifying these sequences and the proteins that bind to them allows understanding of how gene expression and cell processes are hijacked by cancer. For example, LICR research in this area suggests a critical link between lipid synthesis and cell growth and proliferation, the deregulation of which are hallmarks of cancer cells.

Introduction

The regulation of transcription (the copying of DNA into RNA) plays a critical role in cellular responses to environmental stimuli, for example cell growth and proliferation through cell cycle control. Transcriptional regulation is governed by complex interactions between the transcription factor, which binds to the ‘promoter’ sequence at the beginning of each gene, and proteins that bind to regulatory ‘enhancer’, ‘repressor’ and/or ‘insulator’ sequences in the genome. These regulatory sequences define the combinatorial codes that direct and specify gene expression patterns. Identification and characterization of these regulatory sequences are vital to understanding the complex network of gene expression and elucidating the molecular basis of human diseases such as cancers.

Sterol Regulatory Element-Binding Protein Family

The Sterol Regulatory Element-Binding Protein (SREBP) family of transcription factors regulates genes involved in the synthesis of lipids that form cell membranes. To investigate gene regulation by SREBP proteins, LICR scientists from the Uppsala Branch analyzed the expression of key genes involved in lipid metabolism and found that SREBP-mediated transcription was regulated during the cell cycle as a result of specific modifications of the SREBP proteins(1). The team also showed that the SREBP family itself is regulated by a protein, Fbw7, which degrades the SREBPs, thus preventing them from transcribing their target genes(2). Fbw7 - which has been shown to be inactivated in cancers of the breast, endometrium, ovary and colon - also regulates several other proteins vital for cell cycle control. The evidence supports the hypothesis that deregulation of lipid synthesis facilitates the growth and proliferation of cancer cells.

This study indicates that inactivating Fbw7 results in increased expression (by SREBPs) of the LDL receptor gene and enhanced clearance of LDL-cholesterol from the circulation. This unexpected research finding suggests that Fbw7, and in particular its interaction with SREBPs, may be attractive targets for developing new cholesterol-lowering therapies for the fight against cardiovascular disease.

Sox Family and Stem Cell Differentiation

Stem cells are non-specialized cells that have the ability to ‘self-renew’, i.e. divide indefinitely to produce more copies of themselves, and ‘differentiate’, i.e. become a different type of cell. It has been proposed that tumors are actually formed by cancer stem cells, which casts doubt on the efficacy of some cancer therapies that rely on apoptosis (programmed cell death) to which stem cells are particularly resistant.

LICR investigators at the Stockholm Branch are using developing nervous system as a model to understand how stem cells are induced to differentiate or remain in an undifferentiated state. In particular, the team is examining the role of the Sox proteins, a large family of transcription factors that have several regulatory roles during embryonic development. The team first found that the Sox1-3 proteins are important for maintaining neuronal stem cells in an undifferentiated state, and thus maintaining a pool of neural stem cells. The Sox1-3 prevent differentiation by activating neural stem cell-specific gene expression and by inhibiting the activity of proneural bHLH transcription factors (3). Proneural bHLH proteins, the expression of which is controlled by Notch receptor signaling, have important functions in driving the progression of neuronal differentiation.

In a later study, the Stockholm Branch team extended on these data by showing that the Sox21 protein has the opposite effect, and promotes neuronal differentiation by counteracting the activity of the Sox1-3 proteins (4). Together, these findings indicate that the balance of Sox1-3/Sox21 determines whether neural cells remain as precursors or differentiate into neurons. In fact, proneural bHLH proteins promote neuronal differentiation through their ability to up-regulate the expression of Sox21 that, in turn, inhibits the activity of Sox1-3. It is highly plausible that the mechanism governing neural stem cell differentiation has parallels in cancer stem cell differentiation.

References

  1. Bengoechea-Alonso M.T., Punga T., and Ericsson J. Hyperphosphorylation regulates the activity of SREBP1 during mitosis. Proc Natl.Acad.Sci.U.S.A (2005) 102(33):11681-11686.
  2. Sundqvist A., Bengoechea-Alonso M.T., Ye X., Lukiyanchuk V., Jin J., Harper J.W., and Ericsson J. Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7). Cell Metab (2005) 1(6):379-391.
  3. Bylund M., Andersson E., Novitch B.G., and Muhr J. Vertebrate neurogenesis is counteracted by Sox1-3 activity. Nat.Neurosci. (2003) 6(11):1162-1168.
  4. Sandberg M., Kallstrom M., and Muhr J. Sox21 promotes the progression of vertebrate neurogenesis. Nat.Neurosci. (2005) 8(8):995-1001.

Centers Involved in this Research