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Jeffrey C Rathmell

Publications and source records attributed to Jeffrey C Rathmell.

16 recordsLinked to original sources
PubMed2006

Metabolic regulation of Akt: roles reversed.

The respiration-deficient, highly glycolytic metabolic phenotype of cancer cells known as the "Warburg effect" has been appreciated for many years. A new study (see Pelicano et al. on p. 913 of this issue) demonstrates that respiration deficiency caused by mitochondrial mutation or hypoxia may directly promote the enormous survival advantage observed in cancer cells by activation of the phosphatidylinositol 3-kinase-Akt survival pathway. We discuss these and other recent findings that show how metabolic changes associated with cancer can play a significant role in tumor biology.

Cell Survival↗
PubMed2006

Isoform-specific requirement for Akt1 in the developmental regulation of cellular metabolism during lactation.

The metabolic demands and synthetic capacity of the lactating mammary gland exceed that of any other tissue, thereby providing a useful paradigm for understanding the developmental regulation of cellular metabolism. By evaluating mice bearing targeted deletions in Akt1 or Akt2, we demonstrate that Akt1 is specifically required for lactating mice to synthesize sufficient quantities of milk to support their offspring. Whereas cellular proliferation, differentiation, and apoptosis are unaffected, loss of Akt1 disrupts the coordinate regulation of metabolic pathways that normally occurs at the onset of lactation. This results in a failure to upregulate glucose uptake, Glut1 surface localization, lipid synthesis, and multiple lipogenic enzymes, as well as a failure to downregulate lipid catabolic enzymes. These findings demonstrate that Akt1 is required in an isoform-specific manner for orchestrating many of the developmental changes in cellular metabolism that occur at the onset of lactation and establish a role for Akt1 in glucose metabolism.

Animals↗
PubMed2006

Mitochondria, cell death, and B cell tolerance.

To prevent autoimmunity, it is critical that tolerance mechanisms block autoantibody production from self-reactive B cells. B cell tolerance is maintained through mechanisms that can reversibly or irreversibly silence autoreactive B cells. Of these mechanisms, those that lead to B cell death offer the most reliable form of tolerance to prevent autoimmunity. In many cases, death of autoreactive B cells is regulated by the cell intrinsic, or mitochondrial pathway of cell death. The pro-apoptotic Bcl-2 family proteins, Bak, Bax, and Bim have been shown to be required for disruption of mitochondria and intrinsic cell death of self-reactive B cells whereas the anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1 can prevent cell death by interfering with the action of Bax and Bak. Bcl-2 and Bcl-xL have also been shown to regulate the autophagic cell death pathway that may also play a role in B cell tolerance. Even after mitochondrial disruption, mechanisms exist that may impede activation of caspases and death of autoreactive B cells. Together, understanding of cell death mechanisms and how they may affect B cell tolerance has made significant recent advances and it is now important to incorporate alternate and post-mitochondrial cell death mechanisms into B cell tolerance models.

Animals↗
PubMed2005

Lymphocyte selection by starvation: glucose metabolism and cell death.

It has recently been shown by Ciaofani and Zúñiga-Pflücker that the Notch signaling pathway is important in the regulation of thymocyte glucose metabolism during beta-selection. Control of cell metabolism has key roles in the regulation of cell death pathways. Changes in glucose metabolism might affect cell death pathways and be crucial in the development and selection of T lymphocytes.

Animals↗
PubMed2005

Metabolic regulation of oocyte cell death through the CaMKII-mediated phosphorylation of caspase-2.

Vertebrate female reproduction is limited by the oocyte stockpiles acquired during embryonic development. These are gradually depleted over the organism's lifetime through the process of apoptosis. The timer that triggers this cell death is yet to be identified. We used the Xenopus egg/oocyte system to examine the hypothesis that nutrient stores can regulate oocyte viability. We show that pentose-phosphate-pathway generation of NADPH is critical for oocyte survival and that the target of this regulation is caspase-2, previously shown to be required for oocyte death in mice. Pentose-phosphate-pathway-mediated inhibition of cell death was due to the inhibitory phosphorylation of caspase-2 by calcium/calmodulin-dependent protein kinase II (CaMKII). These data suggest that exhaustion of oocyte nutrients, resulting in an inability to generate NADPH, may contribute to ooctye apoptosis. These data also provide unexpected links between oocyte metabolism, CaMKII, and caspase-2.

Animals↗
PubMed2005

T cell homeostasis requires G protein-coupled receptor-mediated access to trophic signals that promote growth and inhibit chemotaxis.

Signals that regulate T cell homeostasis are not fully understood. G protein-coupled receptors (GPCR), such as the chemokine receptors, may affect homeostasis by direct signaling or by guiding T cell migration to distinct location-restricted signals. Here, we show that blockade of Galphai-associated GPCR signaling by treatment with pertussis toxin led to T cell atrophy and shortened life-span in T cell-replete hosts and prevented T cell homeostatic growth and proliferation in T cell-deficient hosts. In vitro, however, neither GPCR inhibition nor chemokine stimulation affected T cell atrophy, survival, or proliferation. These findings suggest that GPCR signals are not trophic stimuli, but instead may be required for migration to distinct trophic signals, such as IL-7 or self-peptide/MHC. Surprisingly, while chemokines did not affect atrophy, atrophic T cells displayed increased chemokine-induced chemotaxis that was prevented by IL-7 and submitogenic anti-CD3 antibody treatment. This increase in migration was associated with increased levels of GTP-bound Rac and the ability to remodel actin. These data suggest a novel mechanism of T cell homeostasis wherein GPCR may promote T cell migration to distinct location-restricted homeostatic trophic cues for T cell survival and growth. Homeostatic trophic signals, in turn, may suppress chemokine sensitivity and cytoskeletal remodeling, to inhibit further migration.

Actins↗
PubMed2004

Cytokine stimulation of aerobic glycolysis in hematopoietic cells exceeds proliferative demand.

The relationship between growth factor-dependent cell growth and proliferation and the up-regulation of cellular metabolism required to support these processes remains poorly defined. Here, we demonstrate that cell growth, proliferation, and glucose metabolism are coordinately regulated by interleukin-3 (IL-3) in cytokine-dependent cells. Surprisingly, glycolytic activity is stimulated to a greater extent than would be expected based on the rate of cell growth or proliferation. IL-3 signaling exerts a direct effect on glycolytic commitment independent of cell growth control. These results are not restricted to IL-3 as the cytokines IL-7 and IL-2 have similar effects on glucose metabolism when assayed in factor-dependent cell lines or primary lymphocytes, respectively. Growth factor stimulation leads cells to consume less oxygen and produce more lactate per glucose, indicative of conversion from oxidative to glycolytic metabolism. The enforced rate of glucose metabolism is in excess of that required to support cell growth; accordingly, if extracellular glucose is reduced, cells retain the ability to grow and proliferate by derepressing oxidative metabolism. These data suggest that the high rate of glycolysis observed in response to growth factor stimulation is a primary effect rather than a homeostatic response to increased cell growth.

Aerobiosis↗
PubMed2004

Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells.

Despite expression of the high-affinity IL-2R, CD4(+)CD25(+) regulatory T cells (Tregs) are hypoproliferative upon IL-2R stimulation in vitro. However the mechanisms by which CD4(+)CD25(+) T cells respond to IL-2 signals are undefined. In this report, we examine the cellular and molecular responses of CD4(+)CD25(+) Tregs to IL-2. IL-2R stimulation results in a G(1) cell cycle arrest, cellular enlargement and increased cellular survival of CD4(+)CD25(+) T cells. We find a distinct pattern of IL-2R signaling in which the Janus kinase/STAT pathway remains intact, whereas IL-2 does not activate downstream targets of phosphatidylinositol 3-kinase. Negative regulation of phosphatidylinositol 3-kinase signaling and IL-2-mediated proliferation of CD4(+)CD25(+) T cells is inversely associated with expression of the phosphatase and tensin homologue deleted on chromosome 10, PTEN.

Animals↗
PubMed2004

B-cell homeostasis: digital survival or analog growth?

Maintenance of B-lymphocyte homeostasis requires balanced cell production, death, and proliferation. To coordinate these processes, B cells are dependent on cell extrinsic signals. In lymphocyte development, precursor cells are dependent on Fms-like tyrosine kinase ligand 3 (Flt3L), and pre-B cells are dependent on the cytokine interleukin-7. Transitional B cells require B-lymphocyte stimulator (BLyS) for survival. Mature B cells require B-cell receptor (BCR) signals and also remain sensitive to their microenvironment. An emerging model suggests that extrinsic signals do not regulate B-cell survival through a digital mechanism where cells are simply instructed to survive or die. Instead, availability and competition for extrinsic signals regulates cellular physiology and metabolism in an analog fashion that then influences cell commitment to apoptosis or proliferation. Decreases in cellular metabolism may sensitize cells to activation and action of the pro-apoptotic Bcl-2 family members, Bak and Bax, and promote apoptosis. In contrast, increases in metabolism may predispose cells to proliferate. Analog control of cell physiology can, thus, be integrated with other inputs by individual cells to produce a fate decision for survival, proliferation, or apoptosis and prevent diseases of cell death, such as immunodeficiency, and cell activation and proliferation, such as autoimmunity or cancer.

Animals↗
PubMed2003

Activated Akt promotes increased resting T cell size, CD28-independent T cell growth, and development of autoimmunity and lymphoma.

The mechanisms that regulate basal T cell size and metabolic activity are uncertain. Since the phosphatidylinositol-3 phosphate kinase (PI3 K) and Akt (PKB) pathway has been shown in model organisms to regulate both cell size and metabolism, we generated transgenic mice expressing a constitutively active form of Akt (myristoylated Akt, mAkt) in T cells. Naive transgenic T cells were enlarged and had increased rates of glycolysis compared to control T cells. In addition, mAkt transgenic T cells resisted death-by-neglect upon in vitro culture. Upon activation, mAkt-transgenic T cells were less dependent than control cells on costimulation through CD28 and could both grow rapidly and secrete cytokines in the absence of CD28 ligation. In addition, transgenic expression of mAkt led to the accumulation of CD4 T cells and B cells with age. Many aged mAkt-transgenic mice also developed autoimmunity with immunoglobulin deposits on kidney glomeruli and displayed increased incidence of lymphoma. Together, these data show that Akt activation is sufficient to increase basal T cell size and metabolism. Enhancement of T cell metabolism by Akt and more rapid CD28-independent T cell growth may contribute to the accumulation of excess immune cells and the development of lymphoma and autoimmunity.

Animals↗
PubMed2003

Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival.

The serine/threonine kinase Akt is a component of many receptor signal transduction pathways and can prevent cell death following growth factor withdrawal. Here, we show that Akt inhibition of cell death is not dependent on new protein translation. Instead, Akt inhibition of cell death requires glucose hydrolysis through glycolysis. Akt was found to regulate multiple steps in glycolysis via posttranscriptional mechanisms that included localization of the glucose transporter, Glut1, to the cell surface and maintenance of hexokinase function in the absence of extrinsic factors. To test the role of glucose uptake and phosphorylation in growth factor-independent survival, cells were transfected with Glut1 and hexokinase 1 (Glut1/HK1) cells. Glut1/HK1 cells accumulated Glut1 on the cell surface and had high glucose uptake capacity similar to that of cells with constitutively active Akt (mAkt). Unlike mAkt-expressing cells, however, they did not consume more glucose, did not maintain prolonged phosphofructokinase-1 protein levels and activity, and did not maintain pentose phosphate shuttle activity in the absence of growth factor. Nevertheless, expression of Glut1 and HK1 promoted increased cytosolic NADH and NADPH levels relative to those of the control cells upon growth factor withdrawal, prevented activation of Bax, and promoted growth factor-independent survival. These data indicate that Bax conformation is sensitive to glucose metabolism and that maintaining glucose uptake and phosphorylation can promote cell survival in the absence of growth factor. Furthermore, Akt required glucose and the ability to perform glycolysis to prevent Bax activation. The prevention of Bax activation by posttranscriptional regulation of glucose metabolism may, therefore, be a required aspect of the ability of Akt to maintain long-term cell survival in the absence of growth factors.

Animals↗
PubMed2002

Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis.

Bak and Bax are required and redundant regulators of an intrinsic mitochondrial cell death pathway. To analyze this pathway in T cell development and homeostasis, we reconstituted mice with Bak(-/-)Bax<(-/-) hematopoietic cells. We found that the development and selection of Bak(-/-)Bax(-/-) thymocytes was disrupted, with altered representation of thymic subsets and resistance to both death-by-neglect and antigen receptor-induced apoptosis. Elimination of Bak(-/-)Bax(-/-) T cells that responded to endogenous superantigen was also reduced. Despite more efficient early reconstitution and apoptotic resistance of Bak(-/-)Bax(-/-) thymocytes, thymic cellularity declined over time. Reduced thymic cellularity resulted from a progressive cessation of thymopoiesis. However, animals developed splenomegaly as a result of accumulated memory T cells that were not deleted after antigen-driven expansion. These data indicate that Bak and Bax are required for thymic selection and peripheral lymphoid homeostasis and suggest that thymopoiesis can be negatively regulated by the accumulation of cells that would normally be eliminated by pro-apoptotic Bcl-2-related genes.

Animals↗
PubMed2002

Pathways of apoptosis in lymphocyte development, homeostasis, and disease.

Apoptosis plays a critical role in lymphocyte development and homeostasis. Enhanced lymphocyte apoptosis can cause immunodeficiency through cell loss. Conversely, inhibition of apoptosis can lead to the development of autoimmunity or lymphoma. Two major pathways contribute to the regulation of lymphocyte cell death, death-by-neglect and death-by-instruction.

Animals↗
PubMed2002

The CD28 signaling pathway regulates glucose metabolism.

Lymphocyte activation initiates a program of cell growth, proliferation, and differentiation that increases metabolic demand. Although T cells increase glucose uptake and glycolysis during an immune response, the signaling pathways that regulate these increases remain largely unknown. Here we show that CD28 costimulation, acting through phosphatidylinositol 3'-kinase (PI3K) and Akt, is required for T cells to increase their glycolytic rate in response to activation. Furthermore, CD28 controls a primary response pathway, inducing a level of glucose uptake and glycolysis in excess of that needed to maintain cellular ATP/ADP levels or macromolecular synthesis. These data suggest that CD28 costimulation functions to increase glycolytic flux, allowing T cells to anticipate energetic and biosynthetic needs associated with a sustained response.

Adenosine Diphosphate↗
PubMed2002

Homeostatic control of lymphocyte survival: potential origins and implications.

Lymphocytes depend on extracellular ligands to maintain their viability. Structurally diverse lymphocyte receptors transmit survival signals through separate signal transduction cascades, which all share the ability to sustain viability by maintaining the sequestration of apoptogenic factors within mitochondria. Receptors can induce cellular survival either by promoting the expression and/or function of anti-apoptotic Bcl-2 family proteins or by activating the phosphatidylinositol-3 kinase Akt pathway. Either of these events represses the function of the pro-apoptotic proteins Bax and Bak, which are required for mitochondrial release of cytochrome c. As we discuss here, the apparently redundant functions of Bax and Bak may have evolved to prevent lymphocyte mitochondria from adapting to loss of receptor mediated signal transduction and thus keep lymphocytes from accumulating in a cell-autonomous manner.

Animals↗