Alternative titles; symbols
HGNC Approved Gene Symbol: STAT5A
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:42,287,439-42,311,943 (from NCBI)
STATs, such as STAT5, are proteins that serve the dual function of signal transducers and activators of transcription in cells exposed to signaling polypeptides (Darnell, 1996).
Hou et al. (1995) cloned the human STAT5 cDNA from an umbilical vein endothelial cell library and found that it encodes a 794-amino acid polypeptide with a predicted mass of approximately 90.5 kD.
Darnell (1996) stated that 6 mouse and human STATs were known (7 if the duplicated STAT5A and STAT5B (604260) genes are considered as 2) and at least STAT1 (600555), STAT3 (102582), and STAT5 exhibit differentially spliced forms.
Ambrosio et al. (2002) cloned the human STAT5A gene. The deduced 794-amino acid protein has an N-terminal DNA-binding domain, followed by a 4-helix bundle, a DNA-binding specificity domain, a connector region, an SH2 domain, and a C-terminal transactivation domain. RT-PCR detected STAT5A expression in all tissues and cell lines examined.
Wang et al. (1996) demonstrated that carboxy-truncated variant Stat5a and Stat5b proteins of 77 and 80 kD, respectively, naturally occur in mouse. These truncated Stat5a and Stat5b forms are derived from incompletely spliced Stat5a and Stat5b transcripts.
By Northern blot analysis, Miyoshi et al. (2001) found that mouse Stat5a is expressed at highest levels in liver and heart, followed by kidney. Weaker expression was detected in most other tissues examined.
Darnell (1996) stated that more than 30 different polypeptides cause STAT activation in various mammalian cells. The most potent activation of STATs through the gp130-containing receptors is of STAT3 and by sequence comparison the wildtype leptin receptor (601007) has potential docking sites for STAT3 molecules. Darnell (1996) reflected on STAT3, STAT5, and STAT6 (601512) as 'fat STATs,' i.e., the involvement of these 3 STATs, but not STAT1, STAT2 (600556), and STAT4 (600558), in the physiologic action of leptin (164160) as described by Ghilardi et al. (1996).
Hou et al. (1995) identified STAT5 as the protein most notably induced in response to T-cell activation with IL2 147680. They hypothesized that STAT5 may govern the effects of IL2 during the immune response.
Ihle and Kerr (1995) reviewed the activation cascade involving the cytokines, the cytokine receptors (see IL2RA; 147730), the Janus kinases (see JAK1; 147795), and the STATs.
Wang et al. (1996) showed that the truncated mouse Stat5a and Stat5b proteins are inducibly tyrosine phosphorylated in the response to several cytokines. These truncated Stat5 proteins form heterodimers with both the full-length wildtype Stat5a and Stat5b proteins. Wang et al. (1996) demonstrated that recombinant truncated forms of Stat5a and Stat5b can be tyrosine phosphorylated and can bind to DNA. The tyrosine phosphorylation of the carboxy-truncated forms was considerably more stable than that of the wildtype Stat5a and Stat5b proteins. Overexpression of a carboxy-truncated Stat5a protein in cells resulted in the specific inhibition of the IL3 (147740)-induced transcriptional activation of the oncostatin M gene (OSM; 165095) and the cytokine-inducible SH2 domain-encoding gene (Cis), both of which have been shown to be normally regulated by Stat5a. Although the truncated Stat5a protein dominantly suppressed the induction of these genes, no effects on cell proliferation were observed. Wang et al. (1996) stated that their results demonstrate the natural existence of potential dominantly suppressive variants of Stat5a and Stat5b, and implicate the carboxyl domains of Stat5a and Stat5b proteins in transcriptional regulation and functions related to dephosphorylation.
Boucheron et al. (1998) examined the DNA-binding domains of mouse Stat5a and Stat5b and determined that the difference in their DNA-binding specificities depends on a critical glycine residue in Stat5b and a critical glutamic residue at a similar position in Stat5a.
To analyze the possible role of STAT5 in human GH-induced proliferation, Friedrichsen et al. (2001) expressed a dominant-negative STAT5 mutant, STAT5A-delta-749, in INS-1 cells under the control of a doxycycline-inducible promoter by stable transfection. Two clones exhibited dose-dependent, doxycycline-inducible expression of STAT5A-delta-749 and suppression of GH-stimulated transcriptional activation of a STAT5-regulated prolactin receptor (PRLR; 176761) promoter-reporter construct. Furthermore, induction of STAT5A-delta-749 expression completely inhibited GH-induced DNA synthesis. Analysis of endogenous gene expression revealed a doxycycline-dependent inhibition of GH-stimulated PRLR and cyclin D2 (123833) mRNA levels. The authors concluded that GH/prolactin-induced beta-cell proliferation is dependent on the JAK2/STAT5 signaling pathway but not the MAPK, PI3K, and PKC signaling pathways.
By searching human chromosomes 21 and 22 for clusters of STAT5-binding sites within regions of interspecies homology, Nelson et al. (2006) identified 4 regions, including 1 within intron 1 of NCAM2 (602040). The authors demonstrated that the NCAM2 site conferred STAT5-dependent transcriptional activity. Neither STAT1 nor STAT3 bound to this region. However, activation of STAT4 and STAT5 resulted in accumulation of both STATs at the NCAM2 regulatory region. Nelson et al. (2006) concluded that NCAM2 is a STAT4- and STAT5-regulated gene and that its expression is regulated by cytokines essential for natural killer cell survival and differentiation.
Zhang et al. (2007) stated that ALK (105590) tyrosine kinase expression is normally confined to neural cells, but chromosomal translocations involving ALK and various partners, most frequently nucleophosmin (NPM1; 164040), result in ectopic expression of ALK in a subset of T-cell lymphomas (TCLs). The NPM1/ALK fusion protein contains the NPM1 oligomerization motif and the ALK catalytic domain, is constitutively activated through autophosphorylation, and mediates malignant cell transformation in vitro and in vivo by activating downstream effectors, including STAT3. Zhang et al. (2007) found that TCL cell lines expressing NPM1/ALK expressed STAT5B, but not STAT5A, protein, whereas normal resting and activated T cells from peripheral blood and ALK-negative TCL cell lines expressed STAT5A protein. Activated NPM1/ALK-positive TCL cell lines also did not express STAT5A mRNA, in spite of having an intact STAT5A gene. Analysis of the CpG island in the STAT5A promoter showed that the region was methylated in NPM1/ALK-positive, but not NPM1/ALK-negative, T cells. Chromatin immunoprecipitation analysis revealed that SP1 (189906) bound the STAT5A promoter in normal activated T cells, whereas MECP2 (300005) bound the promoter of NPM1/ALK-positive TCL cells. Demethylation of the promoter resulted in STAT5A activation and inhibition of NPM1/ALK expression by binding of STAT5A to the NPM1/ALK fusion gene. Expression of NPM1/ALK in NPM1/ALK-negative TCL cells resulted in silencing of STAT5A in a STAT3-dependent manner, whereas small interfering RNA mediated-depletion of NPM1/ALK resulted in STAT5A expression. Zhang et al. (2007) concluded that NPM1/ALK induces epigenetic silencing of the STAT5A gene and that the STAT5A protein can act as a tumor suppressor by inhibiting NPM1/ALK expression.
By yeast 2-hybrid screening of a mouse bone marrow cDNA library, Nakajima et al. (2009) showed that Shd1 (SAC3D1; 618796) interacted with Stat5a and Stat5b. Coimmunoprecipitation assays confirmed these interactions and showed that they were stronger with phosphorylated Stat5, suggesting that Stat5-Shd1 interaction was induced by cytokine stimulation. Mutation analysis showed that the first LxxLL motif of Shd1 was required for Stat5 binding. In cultured mouse pro-B and -T cells, Shd1 was induced by Stat5-activating cytokines. Reporter assays demonstrated that Shd1 repressed Stat5-mediated transcription in a dose-dependent manner without affecting Stat5 stability or phosphorylation. Nakajima et al. (2009) concluded that SHD1 is a cytokine-inducible negative-feedback regulator of STAT5.
Using an inducible promoter, Fatrai et al. (2011) showed that overexpression of STAT5 provided a proliferative advantage for neonatal human hematopoietic stem cells (HSCs), but not stem cell progenitors. Expression profiling identified HIF2A (EPAS1; 603349) among 32 genes that were upregulated by STAT5 overexpression, and HIF2A upregulation was independent of hypoxia. Knockdown of HIF2A in HSCs abrogated the effects of STAT5 on long-term proliferation and self-renewal. HIF2A had no effect on HSC differentiation. Chromatin immunoprecipitation analysis confirmed direct binding of STAT5 to the HIF2A promoter 344 bp upstream of the HIF2A start site. STAT5 overexpression independently resulted in erythroid commitment in megakaryocytic-erythroid progenitors, which was abrogated by knockdown of GATA1 (305371). STAT5 also induced glucose uptake in HSC and progenitor cells via upregulation of the glucose transporters GLUT1 (SLC2A1; 138140) and GLUT3 (SLC2A3; 138170).
Using multiplex, quantitative imaging, Liu et al. (2015) showed that mouse secondary lymphoid tissues contained discrete clusters of highly suppressive regulatory T (Treg) cells expressing phosphorylated Stat5. Within the clusters were rare Il2-positive cells that were activated by self-antigens. The local Il2 induction of Stat5 phosphorylation in Treg cells was part of a feedback circuit that limited further autoimmune responses. Tamoxifen-induced loss of T-cell receptor expression in Treg cells reduced their regulatory capacity and disrupted their localization in clusters, resulting in uncontrolled effector T-cell responses. Liu et al. (2015) concluded that autoreactive T cells are regularly activated to cytokine production and physically cluster with T-cell receptor-stimulated Treg cells responding in a negative-feedback manner to suppress incipient autoimmunity and maintain immune homeostasis.
Chan et al. (2020) analyzed 1,148 patient-derived B-cell leukemia (B-ALL) samples and found that individual mutations did not promote leukemogenesis unless they converged on a single oncogenic pathway characteristic of the differentiation stage of transformed B cells. Mutations that were not aligned with this central oncogenic driver activated divergent pathways and subverted transformation. Oncogenic lesions in B-ALL frequently mimicked signaling through cytokine receptors at the pro-B-cell stage, via activation of STAT5, or pre-B-cell receptors in more mature cells, via activation of ERK (see 601795). STAT5- and ERK-activating lesions were frequent but occurred together in only 3% of cases (P = 2.2 x 10-16). Single-cell mutation and phosphoprotein analyses revealed segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engaged opposing biochemical and transcriptional programs orchestrated by MYC (190080) and BCL6 (109565), respectively. Genetic reactivation of the divergent (i.e., suppressed) pathway came at the expense of the principal oncogenic driver and reversed transformation. Conversely, deletion of divergent pathway components accelerated leukemogenesis. Chan et al. (2020) concluded that persistence of divergent signaling pathways represents a powerful barrier to transformation, whereas convergence on 1 principal driver defines a central event in leukemia initiation. The findings showed that pharmacologic reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver, suggesting that reactivation of divergent pathways may provide a novel strategy to enhance treatment responses.
Ambrosio et al. (2002) determined that the STAT5A gene contains 20 exons. A CpG island covers exon 2, and exon 3 contains the ATG start codon.
Miyoshi et al. (2001) determined that the mouse Stat5a gene contains 20 exons and spans 30 kb. The translation initiation codon is in exon 3, and the stop codon is in exon 20. The mouse Stat5a gene contains a single promoter.
Crispi et al. (2004) determined that both the STAT5A and STAT5B genes lack TATA and CAAT elements, but both have binding sites for transcription factors common in TATA-less promoters. Using a reporter assay, they determined that gene fragments containing the CpG islands were the most transcriptionally active fragments. Sp1 (189906) enhanced expression of the basal promoters, and DNA methylation interfered with Sp1-induced transcription. Cross-species sequence comparison identified a bidirectional negative cis-acting regulatory element in the STAT5 intergenic region.
By FISH, Lin et al. (1996) mapped the STAT5A and STAT5B genes to chromosome 17q11.2. Ambrosio et al. (2002) determined that the STAT5A and STAT5B genes are in an inverted orientation, with their 5-prime ends about 11 kb apart.
Miyoshi et al. (2001) mapped the mouse Stat5a gene to chromosome 11. The promoters of the Stat5a and Stat5b genes are located head to head and are separated by 10 kb. The Stat5a and Stat3 genes are located next to each other in a tail-to-tail orientation with their polyadenylation sites 3 kb apart. The order and orientation of genes at this locus, Ptrf (603189)--Stat3--Stat5a--Stat5b--Lgp1 (608587)--Hcrt (602358), are identical in the syntenic region of human chromosome 17q21.
Socolovsky et al. (1999) studied Stat5a -/- 5b -/- mice during fetal development, a time of rapid growth and little reserve capacity in the erythropoietic system. They found that Stat5a -/- 5b -/- embryos were severely anemic; Stat5a -/- 5b -/- fetal liver erythroid progenitors gave rise to fewer erythroid colonies in vitro and showed a marked increase in their rate of apoptosis. These findings were explained by a crucial role for STAT5 in erythropoietin receptor (EPOR; 133171) antiapoptotic signaling: STAT5 is responsible for the immediate-early induction of the long isoform of the BCL2-related protein (BCLX; 600039) in erythroid cells through direct binding to the promoter of the BCLX gene. This antiapoptotic pathway linking STAT5 activation with direct transcriptional regulation of BCLX suggested a general mechanism whereby STAT proteins may modulate the apoptotic program within the cell, and demonstrated an essential role for STAT5 in cytokine receptor-mediated homeostatic control of the hematopoietic system.
STAT5 is activated in a broad spectrum of human hematologic malignancies. Using a genetic approach, Schwaller et al. (2000) addressed whether activation of STAT5 is necessary for the myelo- and lymphoproliferative disease induced by the TEL (600618)/JAK2 (147796) fusion gene. Whereas mice transplanted with bone marrow transduced with retrovirus expressing TEL/JAK2 developed a rapidly fatal myelo- and lymphoproliferative syndrome, reconstitution with bone marrow derived from Stat5a/b-deficient mice expressing TEL/JAK2 did not induce disease. Disease induction in the Stat5a/b-deficient background was rescued with a bicistronic retrovirus encoding TEL/JAK2 and Stat5a. Furthermore, myeloproliferative disease was induced by reconstitution with bone marrow cells expressing a constitutively active mutant, Stat5a, or a single Stat5a target, murine Osm. These data defined a critical role for STAT5A/B and OSM in the pathogenesis of TEL/JAK2 disease.
Snow et al. (2003) observed that a subset of mice deficient in both Stat5a and Stat5b had dramatic alterations in several bone marrow progenitor populations, along with cellular infiltration of colon, liver, and kidney and early death. The pathology and increased mortality in these mice were abrogated when Rag1 (179615) was also deleted. The phenotype was similar to that in mice defective in Il2 signaling and correlated with a reduction in the number of Cd4 (186940)-positive/Cd25 (IL2RA)-positive regulatory T cells. Snow et al. (2003) concluded that STAT5 is critical for maintenance of tolerance in vivo and that STAT5 is probably activated by IL2R.
Tronche et al. (2004) found that mice with targeted disruption of Gccr (138040) in hepatocytes showed dramatically reduced body size due to impaired Stat5-dependent growth hormone signaling. Mice with a mutant Gccr deficient in DNA binding but still able to interact with Stat5 showed normal body size and normal levels of Stat5-dependent transcription. Tronche et al. (2004) concluded that GCCR acts as a coactivator for STAT5-dependent transcription upon growth hormone stimulation.
Cui et al. (2004) conditionally deleted the 110-kb Stat5 locus, which spans both the Stat5a and Stat5b genes, to study the functions of the Stat5 genes during mouse mammary gland development. Loss of the Stat5 genes prior to pregnancy prevented epithelial proliferation and differentiation. Deletion of Stat5 during pregnancy, after mammary epithelium had entered Stat5-mediated differentiation, resulted in premature cell death, indicating that mammary epithelial cell proliferation, differentiation, and survival require Stat5.
Yao et al. (2006) compared mice with a complete deletion of Stat5a and Stat5b (Stat5 -/-) with mice having an N-terminally truncated, partially functional Stat5 protein (Stat5delN) and mice lacking Il7r (146661), Jak3 (600173), or the common gamma chain, Il2rg (308380). Stat5 -/- mice died before or shortly after birth. Examination of day-18.5 Stat5 -/- embryos showed a severe combined immunodeficiency (SCID; see 601457) phenotype with significantly fewer thymocytes and splenocytes than wildtype controls. The thymocyte deficit in Stat5 -/- embryos was similar in magnitude to that in Il7r- or Il2rg-deficient embryos, whereas Stat5delN embryos had significantly more thymocytes. The splenocyte reduction in Stat5 -/- embryos was more severe than that in Il7r- or IL2rg-deficient mice. B-cell proportions were particularly low in Stat5 -/- embryos compared with controls, similar to Il7r -/- mice. Tcra (see 186880) and Tcrb (see 186930) rearrangement was normal in Stat5 -/- mice, but Tcrg (see 186970) rearrangement was defective. As in Jak3 -/- mice, there was a marked reduction in CD8-positive T cells. Yao et al. (2006) concluded that STAT5 deficiency results in SCID, similar in many respects to what occurs in IL7R, JAK3, or IL2RG deficiency.
Nordstrom et al. (2010) found that, unlike Gh (139250)-deficient mice, loss of Stat5 in mice resulted in increased susceptibility to thrombosis in vivo and to shortened clotting times in vitro. Liver-specific Stat5 deletion also increased thrombosis susceptibility. Increased susceptibility to thrombosis was not due to a secondary increase in Gh secretion. Absence of Stat5 did not alter thrombin generation, but it changed fibrin clot formation and increased fibrin (see 134820) polymerization associated with thrombin-catalyzed rapid release of fibrinopeptide B. Nordstrom et al. (2010) concluded that loss of STAT5 results in a decrease in the concentration of a plasma inhibitor affecting thrombin-triggered cleavage of fibrinopeptide B.
By generating mice with an osteoclast-specific conditional knockout (CKO) of Stat5 Hirose et al. (2014) found that mice with osteoclast-specific conditional knockout of Stat5 had osteoporosis caused by increased bone-resorbing activity of osteoclasts. Stat5-knockout osteoclasts had increased Mapk activity, whereas the Mapk phosphatases Dusp1 (600714) and Dusp2 (603068) were significantly increased. Il3, but not other interleukins, stimulated phosphorylation and nuclear translocation of Stat5 in osteoclasts, and Stat5 expression was upregulated in response to Rankl (TNFSF11; 602642). Hirose et al. (2014) proposed that STAT5 negatively regulates the bone-resorbing function of osteoclasts by promoting DUSP1 and DUSP2 expression and that IL3 promotes STAT5 activation in osteoclasts.
Ambrosio, R., Fimiani, G., Monfregola, J., Sanzari, E., De Felice, N., Salerno, M. C., Pignata, C., D'Urso, M., Ursini, M. V. The structure of human STAT5A and STAT5B genes reveals two regions of nearly identical sequence and an alternative tissue specific STAT5B promoter. Gene 285: 311-318, 2002. [PubMed: 12039059] [Full Text: https://doi.org/10.1016/s0378-1119(02)00421-3]
Boucheron, C., Dumon, S., Santos, S. C. R., Moriggl, R., Hennighausen, L., Gisselbrecht, S., Gouilleux, F. A single amino acid in the DNA binding regions of STAT5A and STAT5B confers distinct binding specificities. J. Biol. Chem. 273: 33936-33941, 1998. [PubMed: 9852045] [Full Text: https://doi.org/10.1074/jbc.273.51.33936]
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Crispi, S., Sanzari, E., Monfregola, J., De Felice, N., Fimiani, G., Ambrosio, R., D'Urso, M., Ursini, M. V. Characterization of the human STAT5A and STAT5B promoters: evidence of a positive and negative mechanism of transcriptional regulation. FEBS Lett. 562: 27-34, 2004. [PubMed: 15043997] [Full Text: https://doi.org/10.1016/S0014-5793(04)00166-8]
Cui, Y., Riedlinger, G., Miyoshi, K., Tang, W., Li, C., Deng, C.-X., Robinson, G. W., Hennighausen, L. Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Molec. Cell. Biol. 24: 8037-8047, 2004. [PubMed: 15340066] [Full Text: https://doi.org/10.1128/MCB.24.18.8037-8047.2004]
Darnell, J. E., Jr. Reflections on STAT3, STAT5, and STAT6 as fat STATs. Proc. Nat. Acad. Sci. 93: 6221-6224, 1996. [PubMed: 8692794] [Full Text: https://doi.org/10.1073/pnas.93.13.6221]
Fatrai, S., Wierenga, A. T. J., Daenen, S. M. G. J., Vellenga, E., Schuringa, J. J. Identification of HIF2-alpha as an important STAT5 target gene in human hematopoietic stem cells. Blood 117: 3320-3330, 2011. [PubMed: 21263150] [Full Text: https://doi.org/10.1182/blood-2010-08-303669]
Friedrichsen, B. N., Galsgaard, E. D., Nielsen, J. H., Moldrup, A. Growth hormone- and prolactin-induced proliferation of insulinoma cells, INS-1, depends on activation of STAT5 (signal transducer and activator of transcription 5). Molec. Endocr. 15: 136-148, 2001. [PubMed: 11145745] [Full Text: https://doi.org/10.1210/mend.15.1.0576]
Ghilardi, N., Ziegler, S., Wiestner, A., Stoffel, R., Heim, M. H., Skoda, R. C. Defective STAT signaling by the leptin receptor in diabetic mice. Proc. Nat. Acad. Sci. 93: 6231-6235, 1996. [PubMed: 8692797] [Full Text: https://doi.org/10.1073/pnas.93.13.6231]
Hirose, J., Masuda, H., Tokuyama, N., Omata, Y., Matsumoto, T., Yasui, T., Kadono, Y., Hennighausen, L., Tanaka, S. Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5-Dusp axis in the osteoclast. J. Exp. Med. 211: 153-163, 2014. [PubMed: 24367002] [Full Text: https://doi.org/10.1084/jem.20130538]
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Liu, Z., Gerner, M. Y., Van Panhuys, N., Levine, A. G., Rudensky, A. Y., Germain, R. N. Immune homeostasis enforced by co-localized effector and regulatory T cells. Nature 528: 225-230, 2015. [PubMed: 26605524] [Full Text: https://doi.org/10.1038/nature16169]
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Nordstrom, S. M., Holliday, B. A., Sos, B. C., Smyth, J. W., Levy, R. E., Dukes, J. W., Lord, S. T., Weiss, E. J. Increased thrombosis susceptibility and altered fibrin formation in STAT5-deficient mice. Blood 116: 5724-5733, 2010. [PubMed: 20823455] [Full Text: https://doi.org/10.1182/blood-2010-06-292227]
Schwaller, J., Parganas, E., Wang, D., Cain, D., Aster, J. C., Williams, I. R., Lee, C.-K., Gerthner, R., Kitamura, T., Frantsve, J., Anastasiadou, E., Loh, M. L., Levy, D. E., Ihle, J. N., Gilliland, D. G. Stat5 is essential for the myelo- and lymphoproliferative disease induced by TEL/JAK2. Molec. Cell 6: 693-704, 2000. [PubMed: 11030348] [Full Text: https://doi.org/10.1016/s1097-2765(00)00067-8]
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Yao, Z., Cui, Y., Watford, W. T., Bream, J. H., Yamaoka, K., Hissong, B. D., Li, D., Durum, S. K., Jiang, Q., Bhandoola, A., Hennighausen, L., O'Shea, J. J. Stat5a/b are essential for normal lymphoid development and differentiation. Proc. Nat. Acad. Sci. 103: 1000-1005, 2006. [PubMed: 16418296] [Full Text: https://doi.org/10.1073/pnas.0507350103]
Zhang, Q., Wang, H. Y., Liu, X., Wasik, M. A. STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression. Nature Med. 13: 1341-1348, 2007. [PubMed: 17922009] [Full Text: https://doi.org/10.1038/nm1659]