Faculty-Anna Lasorella

Cell cycle and differentiation in tumors derived from the nervous system

Loss of differentiation (anaplasia) is frequently linked to uncontrolled proliferation in tumor cells. Our lab studies the role of proteins of the Helix-Loop-Helix (HLH) family, which lack a basic region (Id proteins). The best-known function of these proteins is to inhibit differentiation. Recent experiments in our lab have found that a member of the Id family, Id2, is a natural target of the Retinoblastoma tumor suppressor protein during development of the nervous system. The same Id2 protein is recruited by oncogenes of the Myc family to overcome the tumor suppressor function of the “Rb pathway” in tumors derived from the nervous system.

Specific projects currently in progress include:

- Identify the molecular events directly engaged by Id2 to prevent differentiation and enhance cell cycle progression. Our work suggests that Rb, besides repression of E2F transcription, must restrain these events to act as a cell cycle regulator and suppress tumorigenesis.

- Purify endogenous cellular complexes containing Id proteins in normal and tumor cells and identify functionally relevant Id-associated proteins.

- Generate new mouse models of nervous system malignancies, which recapitulate the deregulated expression of Id proteins in human tumors.

- Establish the role of Id proteins in the natural progression of human nervous system tumors and attempt to identify anti-Id molecules to be used as targeted therapeutic tools for these diseases.

Selected publications:

1) Iavarone A., Garg P., Lasorella A., Hsu J., Israel M.A. The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein. Genes & Dev., 8(11):1270-1284, 1994.

2) Lasorella A., Iavarone A., Israel MA. Id2 specifically alters regulation of the cell cycle by tumor suppressor proteins. Mol. Cell. Biol. 16 (6):2570-2578, 1996.

3) Iavarone A., Massague' J. Repression of the Cdk activator Cdc25A and cell cycle arrest by cytokine TGF-b in cells lacking the Cdk inhibitor pl5. Nature 387: 417-422, 1997.

4) Lasorella A., Noseda M., Beyna M., Iavarone A. Id2 is a target of the retinoblastoma protein and mediates signalling by Myc oncoproteins. Nature (Article), 407:592-598, 2000.

5) Wainwright LJ, Lasorella A, Iavarone A. Distinct mechanisms of cell cycle arrest control the decision between differentiation and senescence in human neuroblastoma cells. Proc Natl Acad Sci U S A 98:9396-9400, 2001.

6) Lasorella A, Uo T, Iavarone A. Id proteins at the cross-road of development and cancer. Oncogene 20:8326-8333, 2001.

7) Lasorella A, Boldrini R, Dominici C, Donfrancesco A, Yokota Y, Inserra A, Iavarone A. Id2 is critical for cellular proliferation and is the oncogenic effector of N-myc in human neuroblastoma. Cancer Res. 62:301-306, 2002.