Hien Tran

Bio: Hien Tran is an academic researcher from Harvard University. The author has contributed to research in topics: FOXO Family & Transcription factor. The author has an hindex of 4, co-authored 5 publications receiving 4931 citations.

Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase

Abstract: The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.

Protein Kinase SGK Mediates Survival Signals by Phosphorylating the Forkhead Transcription Factor FKHRL1 (FOXO3a)

Abstract: Serum- and glucocorticoid-inducible kinases (SGKs) form a novel family of serine/threonine kinases that are activated in response to a variety of extracellular stimuli. SGKs are related to Akt (also called PKB), a serine/threonine kinase that plays a crucial role in promoting cell survival. Like Akt, SGKs are activated by the phosphoinositide-3 kinase (PI3K) and translocate to the nucleus upon growth factor stimulation. However the physiological substrates and cellular functions of SGKs remained to be identified. We hypothesized that SGKs regulate cellular functions in concert with Akt by phosphorylating common targets within the nucleus. The best-characterized nuclear substrates of Akt are transcription factors of the Forkhead family. Akt phosphorylates Forkhead transcription factors such as FKHRL1, leading to FKHRL1's exit from the nucleus and the consequent shutoff of FKHRL1 target genes. We show here that SGK1, like Akt, promotes cell survival and that it does so in part by phosphorylating and inactivating FKHRL1. However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. These findings indicate that SGK acts in concert with Akt to propagate the effects of PI3K activation within the nucleus and to mediate the biological outputs of PI3K signaling, including cell survival and cell cycle progression.

DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein

Abstract: The signaling pathway from phosphoinositide 3-kinase to the protein kinase Akt controls organismal life-span in invertebrates and cell survival and proliferation in mammals by inhibiting the activity of members of the FOXO family of transcription factors. We show that mammalian FOXO3a also functions at the G2 to M checkpoint in the cell cycle and triggers the repair of damaged DNA. By gene array analysis, FOXO3a was found to modulate the expression of several genes that regulate the cellular response to stress at the G2-M checkpoint. The growth arrest and DNA damage response gene Gadd45a appeared to be a direct target of FOXO3a that mediates part of FOXO3a's effects on DNA repair. These findings indicate that in mammals FOXO3a regulates the resistance of cells to stress by inducing DNA repair and thereby may also affect organismal life-span.

The many forks in FOXO's road.

Abstract: The FOXO family of transcription factors constitute an evolutionarily conserved subgroup within the larger family known as winged helix or Forkhead transcriptional regulators. Building upon work in the nematode, researchers have uncovered a role for these proteins in a diverse set of cellular responses that include glucose metabolism, stress response, cell cycle regulation, and apoptosis. At the organismal level, FOXO transcription factors are believed to function in various pathological processes ranging from cancer and diabetes to organismal aging. A number of studies have also shed light on the signaling pathways that regulate FOXO activity in response to external stimuli and have identified multiple FOXO target genes that mediate this varied set of biological responses.

CHAPTER 283 – FOXO Transcription Factors: Key Targets of the PI3K-Akt Pathway That Regulate Cell Proliferation, Survival, and Organismal Aging

Abstract: Publisher Summary Forkhead transcription factors of the FOXO subfamily act as key players in controlling cell cycle progression, cell survival, detoxification, and DNA damage repair by integrating extracellular signals and triggering changes in gene expression. FOXO family members are regulated by the PI3K-Akt pathway in response to growth factor stimulation. Binding of growth factors or insulin to their receptors triggers the activation of the phosphoinositide kinase (PI3K), which in turn is responsible for the activation of several serine/threonine kinases, including serum glucocorticoid inducible kinase (SGK or Akt). The three FOXO regulatory sites are phosphorylated in response to a wide range of stimuli that activate Akt and SGK, including insulin-like growth factor 1 (IGF-1), insulin, interleukin 3, erythropoietin, epidermal growth factor, and transforming growth factor β. The phosphorylation of FOXO transcription factors by Akt and SGK in response to growth factors triggers a change in the subcellular localization of FOXOs. The translocation of FOXOs from the nucleus to the cytoplasm appears to be the primary mechanism of regulation of these transcription factors in response to growth factors. The phosphorylation of the first FOXO regulatory site (Thr 32 in FOXO3a) creates a perfect 14-3-3 binding site, and the phosphorylation of the second FOXO regulatory site (Ser 253 in FOXO3a). FOXOs bind to DNA as a monomer via the Forkhead box, a 100 amino acid region located in the central part of the molecule. The NMR structure of the DBD of FOXO4 shows that this domain adopts a winged helix structure similar to those of the other FOX family members such as FOXA and FOXD.

The phosphatidylinositol 3-Kinase AKT pathway in human cancer.

Abstract: One signal that is overactivated in a wide range of tumour types is the production of a phospholipid, phosphatidylinositol (3,4,5) trisphosphate, by phosphatidylinositol 3-kinase (PI3K) This lipid and the protein kinase that is activated by it — AKT — trigger a cascade of responses, from cell growth and proliferation to survival and motility, that drive tumour progression Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype

Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase

Abstract: The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.