GDF11
Growth differentiation factor 11 (GDF11) also known as bone morphogenetic protein 11 (BMP-11) is a protein that in humans is encoded by the growth differentiation factor 11 gene.[5] GDF11 is a member of the Transforming growth factor beta family.[6]
GDF11 acts as a cytokine and its molecular structure is identical in humans, mice and rats.[7] The bone morphogenetic protein group is characterized by a polybasic proteolytic processing site, which is cleaved to produce a protein containing seven conserved cysteine residues.[8]
Tissue distribution[edit]
GDF11 is expressed in many tissues, including skeletal muscle, pancreas, kidney, nervous system, and retina.[6]
Function[edit]
Gene deletion and over-expression studies indicate that GDF11 primarily regulates the embryological development of the skeletal system. It may also help regulate development of the central nervous system, blood vessels, the kidney and other tissues.[9][10][11][12][13] Reports of GDF11 levels falling with age and functioning as a "rejuvenating factor" when supplemented have been thoroughly refuted (see below) especially as the vast majority of studies indicate that GDF11 levels either do not change with age or may even decrease. In general, GDF11 functions mostly during embryological development, has little function in adults and can have deleterious effects on skeletal muscle, kidneys, bones and the heart during different pathological states.
Effects on cell growth and differentiation[edit]
GDF11 belongs to the transforming growth factor beta superfamily that controls anterior-posterior patterning by regulating the expression of Hox genes.[14] It determines Hox gene expression domains and rostrocaudal identity in the caudal spinal cord.[12]
During mouse development, GDF11 expression begins in the tail bud and caudal neural plate region. GDF knock-out mice display skeletal defects as a result of patterning problems with anterior-posterior positioning.[15] This cytokine also inhibits the proliferation of olfactory receptor neural progenitors to regulate the number of neurons in the olfactory epithelium,[16] and controls the competence of progenitor cells to regulate numbers of retinal ganglionic cells developing in the retina.[17] Other studies in mice suggest that GDF11 is involved in mesodermal formation and neurogenesis during embryonic development.
GDF11 can bind type I TGF-beta superfamily receptors ACVR1B (ALK4), TGFBR1 (ALK5) and ACVR1C (ALK7), but predominantly uses ALK4 and ALK5 for signal transduction.[14] It is also closely related to myostatin, a negative regulator of muscle growth,[18][19] both structurally and phylogenetically.[20]
Effect on cardiac and skeletal muscle aging[edit]
The structure of GDF11 is nearly identical to that of myostatin and both are well known to inhibit different aspects of skeletal and cardiac muscle growth.[21] A research group at Harvard, however, published claims that GDF11 levels in blood fall with age and that supplementing GDF11 can "rejuvenate" old muscle and hearts.[22][23] The group further suggested that GDF11 has actions that oppose those of myostatin. These claims have been soundly and independently refuted by many other academic and industry research groups. The Harvard studies used reagents that have since been invalidated [24][25] and other publications have raised serious questions regarding flaws in the Harvard group's experimental designs and data analyses.[26][27]
A recent review of the controversy [21] suggests that the data discrepancy is likely due to the Harvard group's use of GDF11 peptide that was not biologically active, a result of manufacturing problems. Support for this explanation is provided by the manufacturer itself, which reports GDF11 to have actions opposite from what is expected in the final quality assurance assay. This suggests that the GDF11 used in the Harvard studies may have been acting as a "dominant-negative". It also explains why using genetic tools to manipulate GDF11 expression in muscle and organisms or using GDF11 peptide from other suppliers will inhibit rather than stimulate muscle growth.
It is now known that GDF11 increases with age, that it has deleterious effects on skeletal muscle regeneration and that it is a risk factor for frailty and cardiovascular disease.[28][29] Administrating GDF11 has also been shown to induce the wasting of skeletal and cardiac muscle.[30] By contrast, an antagonist of GDF11 improves heart function in animals with heart failure[31]
Human studies[edit]
It has been reported that GDF11 is down-regulated in pancreatic cancer tissue, compared with surrounding tissue, and pancreatic cell lines exhibit a low expression of the growth factor (65). This group also reported that, in a cohort of 63 PC patients, those with high GDF11 expression had significantly better survival rates in comparison with those with low GDF11 expression. These effects were related to decreased proliferation, migration and invasion, and these observations are in agreement with those reported in HCC and TNBC. GDF11 is also capable of inducing apoptosis in pancreatic cancer cell lines.[32]
However, In 130 patients with colorectal cancer (CRC), the expression of GDF11 was significantly higher compared with normal tissue (56). The classification of the patient cohort in low and high GDF11 expression revealed that those patients with high levels of GDF11 showed a higher frequency of lymph node metastasis, more deaths and lower survival. The study suggests that GDF11 could be a prognostic biomarker in patients with this disease[6]
References[edit]
- ^ a b c GRCh38: Ensembl release 89: ENSG00000135414 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025352 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Ge G, Hopkins DR, Ho WB, Greenspan DS (July 2005). "GDF11 forms a bone morphogenetic protein 1-activated latent complex that can modulate nerve growth factor-induced differentiation of PC12 cells". Molecular and Cellular Biology. 25 (14): 5846–5858. doi:10.1128/MCB.25.14.5846-5858.2005. PMC 1168807. PMID 15988002.
- ^ a b c Simoni-Nieves A, Gerardo-Ramírez M, Pedraza-Vázquez G, Chávez-Rodríguez L, Bucio L, Souza V, et al. (2019). "GDF11 Implications in Cancer Biology and Metabolism. Facts and Controversies". Frontiers in Oncology. 9: 1039. doi:10.3389/fonc.2019.01039. PMC 6803553. PMID 31681577.
- ^ Jamaiyar A, Wan W, Janota DM, Enrick MK, Chilian WM, Yin L (July 2017). "The versatility and paradox of GDF 11". Pharmacology & Therapeutics. 175: 28–34. doi:10.1016/j.pharmthera.2017.02.032. PMC 6319258. PMID 28223232.
- ^ "Gene GDF11". Genecards. Retrieved 25 May 2013.
- ^ Egerman, Marc; Glass, David (2019). "The role of GDF11 in aging and skeletal muscle, cardiac and bone homeostasis". 0 Critical Reviews in Biochemistry and Molecular Biology. 54 (2): 174–183. doi:10.1080/10409238.2019.1610722. PMID 31144559. S2CID 169039791.
- ^ Esquela AF, Lee SJ (May 2003). "Regulation of metanephric kidney development by growth/differentiation factor 11". Developmental Biology. 257 (2): 356–370. doi:10.1016/s0012-1606(03)00100-3. PMID 12729564.
- ^ Dichmann DS, Yassin H, Serup P (November 2006). "Analysis of pancreatic endocrine development in GDF11-deficient mice". Developmental Dynamics. 235 (11): 3016–3025. doi:10.1002/dvdy.20953. PMID 16964608. S2CID 30675774.
- ^ a b Liu JP (August 2006). "The function of growth/differentiation factor 11 (Gdf11) in rostrocaudal patterning of the developing spinal cord". Development. 133 (15): 2865–2874. doi:10.1242/dev.02478. PMID 16790475.
- ^ Gamer LW, Cox KA, Small C, Rosen V (January 2001). "Gdf11 is a negative regulator of chondrogenesis and myogenesis in the developing chick limb". Developmental Biology. 229 (2): 407–420. doi:10.1006/dbio.2000.9981. PMID 11203700.
- ^ a b Andersson O, Reissmann E, Ibáñez CF (August 2006). "Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anterior-posterior axis". EMBO Reports. 7 (8): 831–837. doi:10.1038/sj.embor.7400752. PMC 1525155. PMID 16845371.
- ^ McPherron AC, Lawler AM, Lee SJ (July 1999). "Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11". Nature Genetics. 22 (3): 260–264. doi:10.1038/10320. PMID 10391213. S2CID 1172738.
- ^ Wu HH, Ivkovic S, Murray RC, Jaramillo S, Lyons KM, Johnson JE, Calof AL (January 2003). "Autoregulation of neurogenesis by GDF11". Neuron. 37 (2): 197–207. doi:10.1016/S0896-6273(02)01172-8. PMID 12546816. S2CID 15399794.
- ^ Kim J, Wu HH, Lander AD, Lyons KM, Matzuk MM, Calof AL (June 2005). "GDF11 controls the timing of progenitor cell competence in developing retina". Science. 308 (5730): 1927–1930. Bibcode:2005Sci...308.1927K. doi:10.1126/science.1110175. PMID 15976303. S2CID 42002862.
- ^ McPherron AC, Lee SJ (November 1997). "Double muscling in cattle due to mutations in the myostatin gene". Proceedings of the National Academy of Sciences of the United States of America. 94 (23): 12457–12461. Bibcode:1997PNAS...9412457M. doi:10.1073/pnas.94.23.12457. PMC 24998. PMID 9356471.
- ^ Lee SJ, McPherron AC (October 1999). "Myostatin and the control of skeletal muscle mass". Current Opinion in Genetics & Development. 9 (5): 604–607. doi:10.1016/S0959-437X(99)00004-0. PMID 10508689.
- ^ Kerr, Tovah; Roalson, Eric; Rodgers, Buel (2005). "Phylogenetic analysis of the myostatin gene sub-family and the differential expression of a novel member in zebrafish". Evolution and Development. 7 (5): 390–400. doi:10.1111/j.1525-142X.2005.05044.x. PMID 16174033. S2CID 6538603.
- ^ a b Rodgers, B.; Ward, C. (2022). "Myostatin/Activin Receptor Ligands In Muscle And The Development Status Of Attenuating Drugs". Endocrine Reviews. 43 (2): 329–365. doi:10.1210/endrev/bnab030. PMC 8905337. PMID 34520530.
- ^ Sinha, M.; et al. (2014). "Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle". Science. 344 (6184): 649–652. Bibcode:2014Sci...344..649S. doi:10.1126/science.1251152. PMC 4104429. PMID 24797481.
- ^ Loffredo, F.; et al. (2013). "Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy". Cell. 153 (4): 828–839. doi:10.1016/j.cell.2013.04.015. PMC 3677132. PMID 23663781.
- ^ Rodgers, B.; Eldridge, J. (2015). "Circulating GDF11 Is Unlikely Responsible for Age-Dependent Changes in Mouse Heart, Muscle, and Brain". Endocrinology. 156 (11): 3885–3888. doi:10.1210/en.2015-1628. PMID 26372181. S2CID 3043494.
- ^ Egerman, M.; et al. (2015). "GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration". Cell Metabolism. 22 (1): 164–174. doi:10.1016/j.cmet.2015.05.010. PMC 4497834. PMID 26001423.
- ^ Rodgers, B. (2016). "The Immateriality of Circulating GDF11". Circ Res. 118 (10): 1472–1474. doi:10.1161/CIRCRESAHA.116.308478. PMID 27174947. S2CID 46495961.
- ^ Egerman, M.; Glass, D. (2019). "The role of GDF11 in aging and skeletal muscle, cardiac and bone homeostasis". Crit Rev Biochem Mol Biol. 54 (2): 174–183. doi:10.1080/10409238.2019.1610722. PMID 31144559. S2CID 169039791.
- ^ Schafer, M.; et al. (2016). "Quantification of GDF11 and Myostatin in Human Aging and Cardiovascular Disease". Cell Metab. 23 (6): 1207–1215. doi:10.1016/j.cmet.2016.05.023. PMC 4913514. PMID 27304512.
- ^ Glass, D. (2016). "Elevated GDF11 Is a Risk Factor for Age-Related Frailty and Disease in Humans". Cell Metab. 24 (1): 7–8. doi:10.1016/j.cmet.2016.06.017. PMID 27411004.
- ^ Zimmers, T.; et al. (2017). "Exogenous GDF11 induces cardiac and skeletal muscle dysfunction and wasting". Basic Res Cardiol. 112 (4): 48. doi:10.1007/s00395-017-0639-9. PMC 5833306. PMID 28647906.
- ^ Roh, J.; et al. (2019). "Activin type II receptor signaling in cardiac aging and heart failure". Sci Trans Med. 11 (482). doi:10.1126/scitranslmed.aau8680. PMC 7124007. PMID 30842316.
- ^ Simoni-Nieves A, Gerardo-Ramírez M, Pedraza-Vázquez G, Chávez-Rodríguez L, Bucio L, Souza V, et al. (2019-10-15). "GDF11 Implications in Cancer Biology and Metabolism. Facts and Controversies". Frontiers in Oncology. 9: 1039. doi:10.3389/fonc.2019.01039. PMC 6803553. PMID 31681577.
Further reading[edit]
- Kondás K, Szláma G, Trexler M, Patthy L (August 2008). "Both WFIKKN1 and WFIKKN2 have high affinity for growth and differentiation factors 8 and 11". The Journal of Biological Chemistry. 283 (35): 23677–23684. doi:10.1074/jbc.M803025200. PMC 3259755. PMID 18596030.
- Lee SJ, McPherron AC (October 1999). "Myostatin and the control of skeletal muscle mass". Current Opinion in Genetics & Development. 9 (5): 604–607. doi:10.1016/S0959-437X(99)00004-0. PMID 10508689.
- Hocking JC, Hehr CL, Chang RY, Johnston J, McFarlane S (February 2008). "TGFbeta ligands promote the initiation of retinal ganglion cell dendrites in vitro and in vivo". Molecular and Cellular Neurosciences. 37 (2): 247–260. doi:10.1016/j.mcn.2007.09.011. PMID 17997109. S2CID 140209779.
- Hannan NR, Jamshidi P, Pera MF, Wolvetang EJ (September 2009). "BMP-11 and myostatin support undifferentiated growth of human embryonic stem cells in feeder-free cultures". Cloning and Stem Cells. 11 (3): 427–435. doi:10.1089/clo.2009.0024. PMID 19751112.
- Gamer LW, Wolfman NM, Celeste AJ, Hattersley G, Hewick R, Rosen V (April 1999). "A novel BMP expressed in developing mouse limb, spinal cord, and tail bud is a potent mesoderm inducer in Xenopus embryos". Developmental Biology. 208 (1): 222–232. doi:10.1006/dbio.1998.9191. PMID 10075854.
- Yokoe T, Ohmachi T, Inoue H, Mimori K, Tanaka F, Kusunoki M, Mori M (November 2007). "Clinical significance of growth differentiation factor 11 in colorectal cancer". International Journal of Oncology. 31 (5): 1097–1101. doi:10.3892/ijo.31.5.1097. PMID 17912435.
- Schneyer AL, Sidis Y, Gulati A, Sun JL, Keutmann H, Krasney PA (September 2008). "Differential antagonism of activin, myostatin and growth and differentiation factor 11 by wild-type and mutant follistatin". Endocrinology. 149 (9): 4589–4595. doi:10.1210/en.2008-0259. PMC 2553374. PMID 18535106.
- McPherron AC, Lawler AM, Lee SJ (July 1999). "Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11". Nature Genetics. 22 (3): 260–264. doi:10.1038/10320. PMID 10391213. S2CID 1172738.
- Szumska D, Pieles G, Essalmani R, Bilski M, Mesnard D, Kaur K, et al. (June 2008). "VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5". Genes & Development. 22 (11): 1465–1477. doi:10.1101/gad.479408. PMC 2418583. PMID 18519639.
External links[edit]
- GDF11 human gene location in the UCSC Genome Browser.
- GDF11 human gene details in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: O95390 (Growth/differentiation factor 11) at the PDBe-KB.