Structural Mechanism of Rb Inactivation in Lung Adenocarcinoma

Lung cancer remains the #1 cause of cancer deaths in the U.S. with an estimated 155,000 patients dying in 2017. Smoking contributes to ~85% of lung cancer deaths. Many studies have shown that lung cancer results from deregulation of proteins that control cell division.

Cell growth and division is coordinated through a variety of phases and between these phases are regulatory checkpoints necessary to ensure quality and integrity of the cell. In particular is the transition between the Gap1 (G1) to DNA synthesis (S) phase that once surpassed, the cell is committed to completing the cell cycle. Therefore, control at the G1/S phase transition needs to be highly maintained. The regulation is maintained and coordinated through a variety of interacting proteins. The Retinoblastoma tumor suppressor protein (Rb) arrests the cell in the G1 phase. Transition into the S phase occurs by interaction of Cdk4-CycD with Rb. This interaction causes Rb inactivation and pushes the cell to enter the S phase. Lung cancer cells, and in particular lung adenocarcinoma associated with smoking, typically have levels of Cdk4-CycD that are too high. Understanding how Cdk4-CycD induces passage between G1 to S phase is critical to understanding and treating uncontrollable cell growth, a hallmark of cancer disease.

My proposed project aims to understand how the Rb-Cdk4-CycD interaction occurs and why it is necessary for cell cycle progression. I hypothesize that the association of Cdk4-CycD with Rb changes its molecular structure such that Cdk4-CycD is activated.  This activation of Cdk4-CycD then allows for Rb inactivation and passage of the cell into S phase. To test this hypothesis, I will determine the structure of Rb-Cdk4-CycD in complex and perform Cdk4-CycD activity assays to understand the activation mechanism. Additionally, I will develop an assay and perform a screen that is capable of identifying new inhibitors of Cdk4-CycD.
The Rb-Cdk4-CycD pathway is frequently seen in many tobacco-induced lung cancers and my study will contribute to filling in the gap in understanding mechanistic control between cell cycle phases. Not only will this project help in the overall effort to find a therapeutic for lung cancer, we aim to better inform the general public of what happens within our bodies when tobacco-related products are ingested. TRDRP and the goal of this project aim to expose the risks caused by tobacco-related products and to strive for a tobacco-free California.