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Dissecting the transcriptional mechanisms controlling growth during normal development and cancer

Objective

The main scientific questions addressed in this proposal relate to the understanding of molecular mechanisms of growth control and cancer through the combined use of high-throughput technologies and computational biology. We aim to create a systems-level understanding of the cell cycle, and its regulation by physiological growth factors and oncogenes through the use high-throughput biology to identify all or the majority of genes that are essential for cell cycle progression, and by combining this dataset with computationally predicted and experimentally validated target genes of growth factors and oncogenic pathways. In my opinion, such systems biology approach is critical for understanding of growth control, as organ-specific growth control has proven particularly refractory to genetic dissection. Much of what we know about physiological mechanisms controlling cellular growth in mammals has been revealed by human cancer genetics. These studies have revealed that a large number of genes can contribute to aberrant cell growth; there are more than 300 genes that have been linked to cancer, and mutations found in cancer are often cell type specific ( oncogene preference , i.e. PTCH mutations in medulloblastoma, APC in colon cancer, TMPRSS2-ERG in prostate cancer), suggesting that different pathways in different cell lineages are coupled to the cell cycle machinery. We have preliminary evidence that hedgehog (Hh) and Wnt signals are directly coupled to expression of N-myc and c-Myc genes, but only in tissues and cell-types that display a proliferative response to these factors. Both classical molecular and developmental biology as well as high throughput and systems biological methods will be used for dissection of the molecular mechanism of this selectivity. If successful, these experiments would establish a principle explaining why particular mutations are extremely common in some tumor types but not found at all in others.

Field of science

  • /natural sciences/biological sciences/zoology/mammalogy
  • /natural sciences/biological sciences/developmental biology
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /natural sciences/biological sciences/genetics and heredity
  • /medical and health sciences/clinical medicine/oncology/cancer
  • /medical and health sciences/clinical medicine/oncology/cancer/prostate cancer
  • /medical and health sciences/clinical medicine/oncology/cancer/colorectal cancer

Call for proposal

ERC-2008-AdG
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

KAROLINSKA INSTITUTET
Address
Nobels Vag 5
17177 Stockholm
Sweden
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 200 000
Principal investigator
Anssi Jussi Nikolai Taipale (Prof.)
Administrative Contact
Thomas Tinglöv (Mr.)

Beneficiaries (1)

KAROLINSKA INSTITUTET
Sweden
EU contribution
€ 2 200 000
Address
Nobels Vag 5
17177 Stockholm
Activity type
Higher or Secondary Education Establishments
Principal investigator
Anssi Jussi Nikolai Taipale (Prof.)
Administrative Contact
Thomas Tinglöv (Mr.)