In this proposal we seek to address the Bcl-2-independent molecular mechanisms that regulate the survival of growth factor-deprived cells. Considerable evidence now suggests that mammalian cells are dependent on extracellular signals to maintain the uptake and metabolism of essential nutrients. This dependency limits the ability of both normal and tumor cells to accumulate at non-physiologic sites. We have shown that antiapoptotic Bcl-2 family members can prevent the death of cells deprived of physiologic survival factors. In addition, genetic deletion of the proapoptotic Bcl-2 family members, Bax and Bak, promotes growth factor independent cell survival despite the loss of the ability of cells to take up extracellular nutrients following growth factor withdrawal. How Bcl-2-protected cells adapt bioenergetically to the loss of the ability to take up extracellular nutrients is not well understood. The other major oncogenic cell survival pathway that renders cells growth factor-independent is the PI3K/Akt pathway. Akt promotion of cell survival has been proposed to result from its ability to phosphorylate and suppress the function and/or transcription of BH3 proteins that initiate apoptosis through inactivation of the antiapoptotic Bcl-2 family members. However, unlike the growth factor-independent survival promoted by Bcl-2 family members, survival promoted by Akt remains dependent on a supply of extracellular glucose to protect cells from growth factor deprivation. Despite Akt's potent antiapoptotic role in response to growth factor withdrawal, Akt activation appears to increase cellular sensitivity to cell death in response to treatment with DNA alkylating agents. It is our belief that the current paradigms concerning apoptosis do not provide an explanation for the bioenergetic compromise of cells withdrawn from growth factors in the absence of Bax and Bak, the glucose dependence of Akt-mediated cell survival, and the ability of Akt to increase the cellular sensitivity to cell death in response to DNA alkylating agents. The revised proposal seeks to investigate the molecular explanation for these observations. With these studies, we expect to be able to further define the relationship between growth factor-dependent effects on metabolism and mitochondrial function and the molecular mechanisms by which Bcl-2 proteins and the PI3K/Akt pathway modulate cell survival. Understanding how these antiapoptotic oncogenes regulate cell survival will have an important impact on the understanding of apoptotic regulation. Such knowledge may ultimately help us design novel treatment strategies that exploit the metabolic abnormalities of tumor cells carrying alterations in these two antiapoptotic pathways.
| Olejniczak, Scott H; La Rocca, Gaspare; Radler, Megan R et al. (2016) Coordinated Regulation of Cap-Dependent Translation and MicroRNA Function by Convergent Signaling Pathways. Mol Cell Biol 36:2360-73 |
| Carey, Bryce W; Finley, Lydia W S; Cross, Justin R et al. (2015) Intracellular ?-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518:413-6 |
| La Rocca, Gaspare; Olejniczak, Scott H; González, Alvaro J et al. (2015) In vivo, Argonaute-bound microRNAs exist predominantly in a reservoir of low molecular weight complexes not associated with mRNA. Proc Natl Acad Sci U S A 112:767-72 |
| Ye, Jiangbin; Palm, Wilhelm; Peng, Min et al. (2015) GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2. Genes Dev 29:2331-6 |
| Jiang, Xuejun; Overholtzer, Michael; Thompson, Craig B (2015) Autophagy in cellular metabolism and cancer. J Clin Invest 125:47-54 |
| Zhang, Ji; Fan, Jing; Venneti, Sriram et al. (2014) Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol Cell 56:205-218 |
| Fan, Jing; Ye, Jiangbin; Kamphorst, Jurre J et al. (2014) Quantitative flux analysis reveals folate-dependent NADPH production. Nature 510:298-302 |
| Cheong, Heesun; Wu, Junmin; Gonzales, Linda K et al. (2014) Analysis of a lung defect in autophagy-deficient mouse strains. Autophagy 10:45-56 |
| Ye, Jiangbin; Fan, Jing; Venneti, Sriram et al. (2014) Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov 4:1406-17 |
| Kamphorst, Jurre J; Cross, Justin R; Fan, Jing et al. (2013) Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc Natl Acad Sci U S A 110:8882-7 |
Showing the most recent 10 out of 43 publications
