RESEARCH OVERVIEW

Our laboratory utilizes molecular and genetic approaches to study fundamental biological processes relevant to cancer pathogenesis. We utilize a broad array of technologies that include cellular and molecular biology techniques as mouse genetics and novel targeted drugs. We focus our interests on the promyelocytic leukemia tumor suppressor and oncogenic K-RAS. These genes control processes that are key in oncogenesis such as cell growth regulation, induction of apoptosis and oncogene-induced replicative senescence.

Characterization the role of the Promyelocytic leukemia gene in tumor suppression:

PML is a tumor suppressor inactivated in acute promyelocytic leukemia and the essential component of the PML nuclear body, a macromolecular structure that consists of numerous proteins that play essential roles in tumorigenesis. PML is a well-known inducer of apoptosis and of replicative senescence. Moreover, PML nuclear bodies are disrupted in APL and in other common malignancies.

We have discovered that PML undergoes several post-translational modifications. For example, we found that PML is aberrantly ubiquitinated upon a direct phosphorylation event mediated by the CK2 protein kinase. This event leads to disruption of the nuclear bodies and loss of PML mediated tumor suppression.

We are currently studying how post-translational modification events control PML stability and tumor suppressive function. For these studies we take advantage of an experimental approach that integrates molecular, cellular and mouse genetics techniques.

Cancer Biology, mouse models translational studies:

We study malignancies of the lung and of the hemopoietic system to uncover important genetic alterations that drive tumor initiation, progression and maintenance.

We are focusing our efforts on the study of oncogenic K-RAS induced non-small cell lung cancer and on the characterization of the PI3K signaling pathway in leukemogenesis.

Approaches include tetracycline inducible and Cre/Lox-based conditional genetic systems to generate faithful murine models to study the underlying biology of these tumors.

To complement these studies, we are performing preclinical studies with small molecules that inhibit these signaling pathways and on banked human tumor specimens.