Friday, November 22, 2024
11/22/2024
Project Summary ATF5 is required for the survival of breast cancer cells but is dispensable in their non-transformed counterparts. The reason for ATF5 to have such transformation-dependent pro-survival function is completely unknown. Understanding how ATF5 is uniquely required for the survival of breast cancer cells will new vulnerabilities of cancer cells and help design strategies for their selective construction. Our studies show that ATF5, when phosphorylated by Src and complexed with NFkB, activates the transcription of ATF5, NFkB, and c-Src. Consequently, we hypothesize that 1) NFkB is an obligatory partner for an ATF5-NFkB heterodimer transcription factor, which is responsible for the transcription of ATF5, NFkB, and c-Src; 2) c-Src activates ATF5 by phosphorylating the immunoreceptor tyrosine-based activation motif (ITAM) on ATF5, which creates an auto-stimulatory feedback mechanism sustaining elevated ATF5 and Src activity, perpetuating Src-Ras signaling; and 3) Due to aberrant Src activation in transformed cells, ATF5 is ITAM-phosphorylated, i.e., activated, only in transformed cells. The interdependence between activation of ATF5 and elevated Src-Ras signaling, which promotes cell survival and proliferation of transformed cells, renders ATF5 “addicted” in cancer cells. We will further test the ideas that disruption of ATF5-NFkB interaction or blocking ATF5 ITAM phosphorylation abrogate Ras signaling in transformed cells and cause cell death. Our long-term goal is to determine the molecular mechanism that underlies the transformation-dependent pro-survival function of ATF5 and to develop new strategies to selectively kill breast cancer cells. Here, we propose the two Specific Aims: Aim 1: Determine the mechanism by which ATF5 activates Ras signaling in breast cancer cells. Specifically, we will a) determine how ATF5 and NFkB cooperate to regulate the transcription of the ATF5, NFkB, and c-Src genes in breast cancer cells; b) determine the effect of ATF5 ITAM phosphorylation on ATF5-dependent gene transcription of ATF5, NFkB, and c-Src in breast cancer cells. Aim 2: Selectively destroy breast cancer cells by targeting the ATF5/Ras pathway. Specifically, we will a) determine whether interrupting ATF5-NFkB interaction effectively blocks Ras signaling and induce cell death in transformed HBECs but not in non-transformed HBECs; b) determine whether blocking ATF5 ITAM phosphorylation selectively induces cell death in breast cancer cells and inhibit breast cancer development in mouse models. Completion of these aims will reveal the mechanism that underlies the transformation-dependent pro-survival function of ATF5 and find new strategies for cancer therapy that can selectively destroy breast cancer cells. This research will provide undergraduate students and PharmD students with research opportunities in science and medicine, alleviating a situation in our area—the Inland Northwest—where most of these students have no access to research other than undergraduate laboratory courses.
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