Role of Smad protein in growth inhibition of tumor cells

Institution:	Lawrence Berkeley National Laboratory
Investigator(s):	Kunxin Luo, Ph.D.
Award Cycle:	2000 (Cycle 9)	Grant #: 9RT-0154	Award: $474,492
Subject Area:	Cancer
Award Type:	Research Project Awards

Abstracts

Initial Award Abstract

Tobacco smoking has been shown to be a major cause of lung cancer. It also increases the incidence of other types of cancers. How a normal cell becomes cancerous is a fundamental question that underlies these observations. Therefore, in order to understand how tobacco smoking causes cancer, a better understanding of the basic process and mechanism controlling normal and cancerous cell behavior is critical.

The growth of normal lung cells are tightly regulated by their environment, while lung cancer cells grow in an uncontrolled manner. One of the growth factors that play an important role in the regulation of lung epithelial cell growth is transforming growth factor-ß or TGFß. TGFß can inhibit the growth of normal lung cells and early stage lung cancer cells. Malignant cells often lose the ability to be inhibited by TGFß. Thus, it plays an important role in tumor suppression. TGFß exerts this effect by binding to the surface of cells and by attaching to TGFß receptor molecules. Activated TGFß receptors then signal the cells to inhibit their growth. Inside the cells, a group of proteins called Smad is responsible for transmitting the signals into the nucleus, the “brain” of the cell, and activating a whole series of events that eventually leads to cessation of growth. We have found that, in the nucleus, there is an important protein called SnoN that normally functions to prevent these TGFß-induced events from being active. Smad proteins have to bind to the SnoN protein and get rid of it in order to perform its function. In many cancer cells, Smad proteins were not able to destroy the SnoN protein, thus they may not be able to activate TGFß-induced events. Therefore, interaction between the Smads and SnoN may be the “gate-keeper” between normal and cancer cells and certainly plays an important role in the determination of state of cell growth. However, it is not yet clear how this interaction results in destruction of the SnoN protein, and whether this is critical for carcinogenesis. In this proposal, we will employ molecular biological, biochemical and cell biological approaches to investigate the detail interaction between SnoN and the Smads, and try to understand how deregulation of this interaction results in cancer. We will also uncover the mechanism by which Smad proteins destroy SnoN to inhibit cell growth. Hopefully, the results from this research will lead to better diagnosis and treatment of cancer.

Publications

Smad3 recruits the anaphase promoting complex for ubiquitination and degradation of SnoN.
Periodical: Genes and Development			Index Medicus:
Authors: Stroschein SL, Bonni S, Wrana JL, and Luo K				ART
Yr: 2991	Vol: 15	Nbr:	Abs:	Pg: 2822-2836

The transforming activity of ski is dependent on their ablity to interact with the smad proteins.
Periodical: Journal of Biological Chemistry			Index Medicus:
Authors: He J, Tegen S, Martin SG and Luo K				ART
Yr: 2002	Vol: 278	Nbr:	Abs:	Pg: 30540-30547

Negative regulation of BMP/TGFbeta signaling by the ski family of oncoproteins.
Periodical: Journal of Bone and Joint Surgery			Index Medicus:
Authors: Luo K				ART
Yr: 2003	Vol: 85-A Suppl	Nbr: 3	Abs:	Pg: 39-43

Ski and SnoN: negative regulartors of TGFbeta signaling.
Periodical: Current Opinion Genetic Development			Index Medicus:
Authors: Luo K				ART
Yr: 2004	Vol: 14	Nbr:	Abs:	Pg: 65-70

Smad3 recruits the anaphase promoting complex for ubiquitination and degradation of SnoN.
Periodical: Genes and Development			Index Medicus:
Authors: Stroschein SL, Bonni S, Wrana JL, and Luo K				ART
Yr: 2991	Vol: 15	Nbr:	Abs:	Pg: 2822-2836

The transforming activity of ski is dependent on their ablity to interact with the smad proteins.
Periodical: Journal of Biological Chemistry			Index Medicus:
Authors: He J, Tegen S, Martin SG and Luo K				ART
Yr: 2002	Vol: 278	Nbr:	Abs:	Pg: 30540-30547

Negative regulation of BMP/TGFbeta signaling by the ski family of oncoproteins.
Periodical: Journal of Bone and Joint Surgery			Index Medicus:
Authors: Luo K				ART
Yr: 2003	Vol: 85-A Suppl	Nbr: 3	Abs:	Pg: 39-43

Ski and SnoN: negative regulartors of TGFbeta signaling.
Periodical: Current Opinion Genetic Development			Index Medicus:
Authors: Luo K				ART
Yr: 2004	Vol: 14	Nbr:	Abs:	Pg: 65-70