RAS-MEDIATED PROTEOLYSIS/ONCOGENESIS

Signaling pathways are indispensable for cellular communications that control proper development of multicellular organisms. Cancer cells undergo active proliferation. The central importance of the RAS signal transduction in promoting cell proliferation, neoplastic transformation, and oncogenesis is well established.

Our research focuses on the RAS pathway that commonly becomes hyperactivated during human cancer development. The abnormal form of RAS protein – its oncogenic form, acts like "a gas pedal that is permanently stuck in the ACCELERATION position in a car". We attempt to stop "such a runaway car" (i.e. a cancer cell) by attacking "its downstream transmission system" (i.e. the cellular machinery that brings about the destruction of proteins that promote cancer growth in response to inappropriate RAS activation signal).

Since the RAS signaling pathway is highly conserved in all multicellular organisms, our work on the molecular control of the ON/OFF switch governing the "RAS-dependent cell proliferation engine" should contribute to our understanding of the role that RAS plays in promoting human cancer initiation and progression.

Figure 1. RAS Pathway

RAS proteins are evolutionarily conserved small GTPases that transmit signals from receptor tyrosine kinases (RTKs) to the nucleus through multiple effector pathways, among them the RAF/MEK/MAPK kinase cascade, phosphatidylinositol 3-kinase (PI3K/AKT) and the Ral-GEF signaling pathway. The RAS signal transduction has a demonstrated importance in cell proliferation, differentiation and apoptosis.

Oncogenic RAS proteins, which are hyperactived forms of RAS, are among the most common genetic alterations detected in human cancer. For example, oncogenic RAS mutations are found in > 95% pancreatic adenocarcinomas, ~50-60% of colorectal and thyroid cancers, ~70% malignant neoplasias and ~30% of all human cancers. Since many key components and aspects of the RAS signaling pathway are evolutionarily conserved, our work specifically focuses on a downstream component of RAS signaling, namely SEVEN-IN-ABSENTIA (SINA), which encodes an evolutionarily conserved family of E3 ubiquitin ligases.

Development, March 2001 cover reprinted with permission.

The human homologues of SINA (SIAHs) have been implicated in a diverse array of cellular processes, including neuronal differentiation, apoptosis, tumor suppression, β-catenin, APC and p53 signaling. Since both RAS and many of the known SIAH substrates have a demonstrated role in oncogenesis, components of the SIAH-dependent proteolytic pathway may serve as novel targets for proteosome-based anticancer therapies and contribute to our understanding of the role of RAS-regulated proteolysis signals in the genesis of human cancer. Ultimately, we hope to develop a novel anticancer therapy that can specifically inhibit oncogenic RAS activity and block cancer cell growth in cancer.

The objectives of this research project are:

1. Determine the biological function and regulation of SINA-dependent proteolysis in RAS signaling in development.
2. Identify new SINA/SIAH pathway components and elucidate the molecular mechanism by which SINA/SIAH targets substrates for degradation.
3. Determine whether mammalian SINA homologues (SIAHs) participate in RAS-mediated oncogenesis, and investigate how the SIAH-dependent proteolysis promotes cancer cell growth, differentiation and apoptosis in human cancers (human pancreatic and prostate cancer in particular).