Protein BTG2 explained

Protein BTG2 also known as BTG family member 2 or NGF-inducible anti-proliferative protein PC3 or NGF-inducible protein TIS21, is a protein that in humans is encoded by the BTG2 gene (B-cell translocation gene 2)[1] and in other mammals by the homologous Btg2 gene.[2] [3] This protein controls cell cycle progression and proneural genes expression by acting as a transcription coregulator that enhances or inhibits the activity of transcription factors.

The protein BTG2 is the human homolog of the PC3 (pheochromocytoma cell 3) protein in rat and of the Tis21 (tetradecanoyl phorbol acetate-inducible sequence 21) protein in mouse.[4] [5] Tis21 had been originally isolated as a sequence induced by TPA in mouse fibroblasts,[3] whereas PC3 was originally isolated as sequence induced at the beginning of neuron differentiation;[2] BTG2 was then isolated in human cells as sequence induced by p53 and DNA damage.[1] [6]

The protein encoded by the gene BTG2 (which is the official name assigned to the gene PC3/Tis21/BTG2) is a member of the BTG/Tob family (that comprises six proteins BTG1, BTG2/PC3/Tis21, BTG3/ANA, BTG4/PC3B, Tob1/Tob and Tob2).[4] [5] [7] This family has structurally related proteins that appear to have antiproliferative properties. In particular, the BTG2 protein has been shown to negatively control a cell cycle checkpoint at the G1 to S phase transition in fibroblasts and neuronal cells by direct inhibition of the activity of cyclin D1 promoter.[8] [9] [10]

Regulator of neuron differentiation

A number of studies in vivo have shown that BTG2 expression is associated with the neurogenic asymmetric division in neural progenitor cells.[11] [12] [13] [14] [15] Tis21-GFP has been used as a neurogenic marker because it is not expressed until neurogenesis begins, is present in almost all early-born neurons, and interacts with neuron producing intermediate progenitor cells.[16] Moreover, when directly overexpressed in vivo in neural progenitor cells, BTG2 induces their differentiation.[17] [18] In fact, in the neuronal PC12 cell line BTG2 is not able to trigger differentiation by itself, but only to synergize with NGF,[19] [20] while in vivo BTG2 is fully able to induce differentiation of progenitor cells, i.e., during embryonic development in the neuroblast of the neural tube and in granule precursors of cerebellum, as well in adult progenitor cells of the dentate gyrus and of the subventricular zone.[17] [18] Notably, it has recently been shown that BTG2 is essential for the differentiation of new neurons, using a BTG2 knock out mouse.[21] BTG2 is thus a pan-neural gene required for the development of the new neurons generated during adulthood, in the two neurogenic regions of adult brain, i.e., the hippocampus and the subventricular zone.[21] Such requirement of BTG2 in neuron maturation is consistent with the fact that during brain development BTG2 is expressed in the proliferating neuroblasts of the ventricular zone of the neural tube, and to a lower extent in the differentiating neuroblasts of the mantle zone; postnatally it is expressed in cerebellar precursors mainly in the proliferating regions of the neuropithelium (i.e., in the external granular layer), and in the hippocampus in proliferating and differentiating progenitor cells.[11] [17] [18] The pro-differentiative action of BTG2 appears to be consequent not only to inhibition of cell cycle progression but also to a BTG2-dependent activation of proneural genes in neural progenitor cells.[17] [21] In fact, BTG2 activates proneural genes by associating with the promoter of Id3, a key inhibitor of proneural gene activity, and by negatively regulating its activity.[21]

BTG2 is a transcriptional cofactor, given that it has been shown to associate with, and regulate the promoters not only of Id3 but also of cyclin D1 and RAR-β, being part of transcriptional complexes.[10] [22] [23] It has been shown that when the differentiation of new neurons of the hippocampus - a brain region important for learning and memory - is either accelerated or delayed by means of overexpression or deletion of BTG2, respectively, spatial and contextual memory is heavily altered.[18] [21] This suggests that the time the young neurons spend in different states of neuronal differentiation is critical for their ultimate function in learning and memory, and that BTG2 may play a role in the timing of recruitment of the new neuron into memory circuits.[18] [21]

In conclusion, the main action of Btg2 on neural progenitor cells of the dentate gyrus and subventricular zone during adult neurogenesis is the positive control of their terminal differentiation (see for review:[24]). During the early postnatal development of the cerebellum, Btg2 is mainly required to control the migration and differentiation of the precursor cells of cerebellar granule neurons.[25] In contrast, BTG1, the closest homolog to Btg2, appears to negatively regulate the proliferation of adult stem cells in the dentate gyrus and subventricular zone, maintaining in quiescence the stem cells pool and preserving it from depletion.[26] [27] BTG1 is also necessary to limit the proliferative expansion of cerebellar precursor cells, as without BTG1 the adult cerebellum is larger and unable to coordinate motor activity.[28]

Medulloblastoma suppressor

BTG2 has been shown to inhibit medulloblastoma, the very aggressive tumor of cerebellum, by inhibiting the proliferation and triggering the differentiation of the precursors of cerebellar granule neurons. This demonstration was obtained by overexpressing BTG2 in a mouse model of medulloblastoma, presenting activation of the sonic hedgehog pathway (heterozygous for the gene Patched1).[10] More recently, it has been shown that the ablation of BTG2 greatly enhances the medulloblastoma frequency by inhibiting the migration of cerebellar granule neuron precursors. This impairment of migration of the precursors of cerebellar granule neurons forces them to remain at the surface of the cerebellum, where they continue to proliferate, becoming target of transforming insults.[29] The impairment of migration of the precursors of cerebellar granule neurons (GCPs) depends on the inhibition of expression of the chemokine CXCL3 consequent to ablation of BTG2. In fact, the transcription of CXCL3 is directly regulated by BTG2, and CXCL3 is able to induce cell-autonomously the migration of cerebellar granule precursors. Treatment with CXCL3 prevents the growth of medulloblastoma lesions in a Shh-type mouse model of medulloblastoma.[30] Thus, CXCL3 is a target for medulloblastoma therapy.[29]

Interactions

BTG2 has been shown to interact with PRMT1, HOXB9,[31] [32] CNOT8[33] and HDAC1 HDAC4 and HDAC9.[34] [10] It has also been studied with Pax6 and Tbr2 when observing the role of Tis21 in neurogenic divisions.

Further reading

Notes and References

  1. Rouault JP, Falette N, Guéhenneux F, Guillot C, Rimokh R, Wang Q, Berthet C, Moyret-Lalle C, Savatier P, Pain B, Shaw P, Berger R, Samarut J, Magaud JP, Ozturk M, Samarut C, Puisieux A . Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway . Nature Genetics . 14 . 4 . 482–6 . December 1996 . 8944033 . 10.1038/ng1296-482 . 11693/49026 . 20119529 . free .
  2. Bradbury A, Possenti R, Shooter EM, Tirone F . Molecular cloning of PC3, a putatively secreted protein whose mRNA is induced by nerve growth factor and depolarization . Proceedings of the National Academy of Sciences of the United States of America . 88 . 8 . 3353–7 . April 1991 . 1849653 . 51445 . 10.1073/pnas.88.8.3353 . 1991PNAS...88.3353B . free .
  3. Fletcher BS, Lim RW, Varnum BC, Kujubu DA, Koski RA, Herschman HR . Structure and expression of TIS21, a primary response gene induced by growth factors and tumor promoters . The Journal of Biological Chemistry . 266 . 22 . 14511–8 . August 1991 . 10.1016/S0021-9258(18)98716-8 . 1713584 . free .
  4. Matsuda S, Rouault J, Magaud J, Berthet C . In search of a function for the TIS21/PC3/BTG1/TOB family . FEBS Letters . 497 . 2–3 . 67–72 . May 2001 . 11377414 . 10.1016/S0014-5793(01)02436-X . free . 2001FEBSL.497...67M .
  5. Tirone F . The gene PC3(TIS21/BTG2), prototype member of the PC3/BTG/TOB family: regulator in control of cell growth, differentiation, and DNA repair? . Journal of Cellular Physiology . 187 . 2 . 155–65 . May 2001 . 11267995 . 10.1002/jcp.1062 . free .
  6. Web site: Entrez Gene: BTG2 BTG family, member 2.
  7. Winkler GS . The mammalian anti-proliferative BTG/Tob protein family . Journal of Cellular Physiology . 222 . 1 . 66–72 . January 2010 . 19746446 . 10.1002/jcp.21919 . 3436967 .
  8. Montagnoli A, Guardavaccaro D, Starace G, Tirone F . Overexpression of the nerve growth factor-inducible PC3 immediate early gene is associated with growth inhibition . Cell Growth & Differentiation . 7 . 10 . 1327–36 . October 1996 . 8891336 . 2010-03-16 . 2015-05-18 . https://web.archive.org/web/20150518091134/http://cgd.aacrjournals.org/cgi/content/abstract/7/10/1327 . dead .
  9. Guardavaccaro D, Corrente G, Covone F, Micheli L, D'Agnano I, Starace G, Caruso M, Tirone F . Arrest of G(1)-S progression by the p53-inducible gene PC3 is Rb dependent and relies on the inhibition of cyclin D1 transcription . Molecular and Cellular Biology . 20 . 5 . 1797–815 . March 2000 . 10669755 . 85361 . 10.1128/MCB.20.5.1797-1815.2000 .
  10. Farioli-Vecchioli S, Tanori M, Micheli L, Mancuso M, Leonardi L, Saran A, Ciotti MT, Ferretti E, Gulino A, Pazzaglia S, Tirone F . Inhibition of medulloblastoma tumorigenesis by the antiproliferative and pro-differentiative gene PC3 . FASEB Journal . 21 . 9 . 2215–25 . July 2007 . 17371797 . 10.1096/fj.06-7548com . free . 4974360 .
  11. Iacopetti P, Barsacchi G, Tirone F, Maffei L, Cremisi F . Developmental expression of PC3 gene is correlated with neuronal cell birthday . Mechanisms of Development . 47 . 2 . 127–37 . August 1994 . 7811636 . 10.1016/0925-4773(94)90085-X . 46597681 . https://web.archive.org/web/20110722030411/http://gcpd.inmm.cnr.it/pdfs/PC3%20marker%20of%20newborn%20neurons%20-%20MechDev%201994.pdf . dead . 2011-07-22 .
  12. Iacopetti P, Michelini M, Stuckmann I, Oback B, Aaku-Saraste E, Huttner WB . Expression of the antiproliferative gene TIS21 at the onset of neurogenesis identifies single neuroepithelial cells that switch from proliferative to neuron-generating division . Proceedings of the National Academy of Sciences of the United States of America . 96 . 8 . 4639–44 . April 1999 . 10200315 . 16385 . 10.1073/pnas.96.8.4639 . 1999PNAS...96.4639I . free .
  13. Haubensak W, Attardo A, Denk W, Huttner WB . Neurons arise in the basal neuroepithelium of the early mammalian telencephalon: a major site of neurogenesis . Proceedings of the National Academy of Sciences of the United States of America . 101 . 9 . 3196–201 . March 2004 . 14963232 . 365766 . 10.1073/pnas.0308600100 . free .
  14. Calegari F, Haubensak W, Haffner C, Huttner WB . Selective lengthening of the cell cycle in the neurogenic subpopulation of neural progenitor cells during mouse brain development . The Journal of Neuroscience . 25 . 28 . 6533–8 . July 2005 . 16014714 . 6725437 . 10.1523/JNEUROSCI.0778-05.2005 .
  15. Götz M, Huttner WB . The cell biology of neurogenesis . Nature Reviews Molecular Cell Biology . 6 . 10 . 777–88 . October 2005 . 16314867 . 10.1038/nrm1739 . 16955231 .
  16. Kowalczyk. Tom. Pontious. Adria. Englund. Chris. Daza. Ray A. M.. Bedogni. Francesco. Hodge. Rebecca. Attardo. Alessio. Bell. Chris. Huttner. Wieland B.. 2009-10-01. Intermediate Neuronal Progenitors (Basal Progenitors) Produce Pyramidal–Projection Neurons for All Layers of Cerebral Cortex. Cerebral Cortex. en. 19. 10. 2439–2450. 10.1093/cercor/bhn260. 19168665. 1047-3211. 2742596.
  17. Canzoniere D, Farioli-Vecchioli S, Conti F, Ciotti MT, Tata AM, Augusti-Tocco G, Mattei E, Lakshmana MK, Krizhanovsky V, Reeves SA, Giovannoni R, Castano F, Servadio A, Ben-Arie N, Tirone F . Dual control of neurogenesis by PC3 through cell cycle inhibition and induction of Math1 . The Journal of Neuroscience . 24 . 13 . 3355–69 . March 2004 . 15056715 . 6730030 . 10.1523/JNEUROSCI.3860-03.2004 .
  18. Farioli-Vecchioli S, Saraulli D, Costanzi M, Pacioni S, Cinà I, Aceti M, Micheli L, Bacci A, Cestari V, Tirone F . The timing of differentiation of adult hippocampal neurons is crucial for spatial memory . PLOS Biology . 6 . 10 . e246 . October 2008 . 18842068 . 2561078 . 10.1371/journal.pbio.0060246 . free .
  19. Corrente G, Guardavaccaro D, Tirone F . PC3 potentiates NGF-induced differentiation and protects neurons from apoptosis . NeuroReport . 13 . 4 . 417–22 . March 2002 . 11930152 . 10.1097/00001756-200203250-00011 . 4996878 .
  20. el-Ghissassi F, Valsesia-Wittmann S, Falette N, Duriez C, Walden PD, Puisieux A . BTG2(TIS21/PC3) induces neuronal differentiation and prevents apoptosis of terminally differentiated PC12 cells . Oncogene . 21 . 44 . 6772–78 . October 2002 . 12360398 . 10.1038/sj.onc.1205888 . free .
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  23. Lin WJ, Gary JD, Yang MC, Clarke S, Herschman HR . The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferase . The Journal of Biological Chemistry . 271 . 25 . 15034–44 . June 1996 . 8663146 . 10.1074/jbc.271.25.15034 . free .
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  25. Ceccarelli M, Micheli L, D'Andrea G, De Bardi M, Scheijen B, Ciotti M, Leonardi L, Luvisetto S, Tirone F . Altered cerebellum development and impaired motor coordination in mice lacking the Btg1 gene: Involvement of cyclin D1 . Developmental Biology . 408 . 1 . 109–25 . December 2015 . 26524254 . 10.1016/j.ydbio.2015.10.007 . free .
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  34. Micheli L, D'Andrea G, Leonardi L, Tirone F . HDAC1, HDAC4, and HDAC9 Bind to PC3/Tis21/Btg2 and Are Required for Its Inhibition of Cell Cycle Progression and Cyclin D1 Expression . Journal of Cellular Physiology . 232 . 7 . 1696–1707 . 2017 . 10.1002/jcp.25467 . 27333946 . 4070837 .

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