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:
1. 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.
2. Purify endogenous cellular complexes containing Id proteins in normal and tumor cells and identify functionally relevant Id-associated proteins.
3. Generate new mouse models of nervous system malignancies, which recapitulate the deregulated expression of Id proteins in human tumors.
4. 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.
1. Zhao X, D' Arca D, Lim WK, Brahmachary M, Carro MS, Ludwig T, Cardo CC, Guillemot F, Aldape K, Califano A, Iavarone A
, Lasorella A. The N-Myc-DLL3 Cascade Is Suppressed by the Ubiquitin Ligase Huwe1 to Inhibit Proliferation and Promote Neurogenesis in the Developing Brain. Dev Cell. 2009
2. Zhao X, Heng JI, Guardavaccaro D, Jiang R, Pagano M, Guillemot F, Iavarone A
, Lasorella A. The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nat Cell Biol. 2008
Jun;10(6):643-53. Epub 2008 May 18.
3. Guardavaccaro D, Frescas D, Dorrello NV, Peschiaroli A, Multani AS, Cardozo T, Lasorella A, Iavarone A
, Chang S, Hernando E, Pagano M. Control of chromosome stability by the beta-TrCP-REST-Mad2 axis. Nature. 2008
4. Iavarone A, Lasorella A
. ID proteins as targets in cancer and tools in neurobiology. Trends Mol Med. 2006
Dec;12(12):588-94. Epub 2006 Oct 30. Review.
5. Lasorella A, Stegmuller J, Guardavaccaro D, Liu G, Carro MS, Rothschild G, de la Torre-Ubieta L, Pagano M, Bonni A, Iavarone A
. Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature. 2006
Jul 27;442(7101):471-4. Epub 2006 Jun 28.
6. Rothschild G, Zhao X, Iavarone A
, Lasorella A. E Proteins and Id2 converge on p57Kip2 to regulate cell cycle in neural cells. Mol Cell Biol. 2006
7. Lasorella A, Iavarone A
. The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system. Proc Natl Acad Sci U S A. 2006
Mar 28;103(13):4976-81. Epub 2006 Mar 20.
8. 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.