Abstract
The proto-oncogene Trks encode the high-affinity receptor tyrosine kinases f or neurotrophins of a nerve growth factor (NGF) family. The Trk signals spa tiotemporally regulate neural development and maintenance of neural network. However, Trk was originally cloned as an oncogene fused with the tropomyosi n gene in the extracellular domain. Accumulating evidence has demonstrated that the rearranged Trk oncogene is often observed in non-neuronal neoplasms such as colon and papillary thyroid cancers, while the signals through the r eceptors encoded by the proto-oncogene Trks regulate growth, differentiation and apoptosis of the tumors with neuronal origin such as neuroblastoma and m edulloblastoma. The intracellular Trk signaling pathway is also different d epending on the Trk family receptors, cell types and the grade of transforma tion. Furthermore, developmentally programmed cell death of neuron, which i s largely regulated by neurotrophin signaling, is at least in part controlle d by tumor suppressors p53 and p73 as well as their antagonist deltaNp73. T hus, the Trks and their downstream signaling function in both ontogenesis an d oncogenesis. In this short review, the dynamic role of the Trk family rec eptors signaling in neural development, neurogenic tumors and other cancers will be discussed.

Introduction
Trk is a receptor tyrosine kinase which primarily regulates growth, differe ntiation and programmed cell death of neurons in both peripheral and central nervous systems. The Trk gene, however, has originally been cloned as an on cogene fused with the tropomyosin gene in the extracellular domain, conferri ng constitutive activation of its tyrosine kinase activity to induce continu ous proliferation of the cell. It was a great surprise when proto-oncogene Trk was found to be a high-affinity receptor for nerve growth factor (NGF) w hich plays a key role in regulating differentiation and programmed cell deat h during neural development. Nevertheless, the molecular basis of NGF/Trk signaling and its role in cancer have long been mysterious especially in neoplasms of nervous system such as neuroblastoma and medulloblastoma.

The recent investigations have just started to unveil the fact that NGF/Trk signaling is regulated by connecting a variety of intracellular signaling cascades which include protein products encoded by proto-oncogenes and tumor suppressor genes, most of which are indispensable for both neural development and tumorigenesis. In this review, the role of the oncogene Trk as well as that of the proto-oncogene Trk in human cancers is discussed in conjunction with the recent observations which link them to other cancer-related genes, p53 and p73.

Trk signaling regulates neuronal survival and differentiation
The discovery by Rita Levi-Montalcini and Vitor Hamburger of nerve growth factor (NGF) more than four decades ago has opened the door to understanding important role of soluble factors and their receptors in normal ontogeny [1] . However, the NGF function has not been unveiled until the proto-oncogene TrkA was found to encode the high-affinity receptor [2, 3]. The other NGF r eceptor was identified as p75NTR which bound to NGF with low affinity [4]. Now, neurotrophin family of growth factors consists of NGF, brain-derived ne urtrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5 ). Further work has identified family members of the high-affinity neurotro phin receptors with tyrosine kinase activity, TrkA, TrkB, and TrkC, to which neurotrophins bind differently [5] (Fig. 1). TrkA is the preferred receptor for NGF, TrkB for BDNF and NT-4/5, and TrkC for NT-3. All of the neurotroph ins also bind, similarly and with much lower affinity, to p75NTR, a member o f tumor necrosis factor receptor (TNFR)/Fas family [5]. The results obtaine d from the gene targeting analyses have revealed function of each neurotroph in or receptor in vivo [6]. NGF/TrkA signaling supports survival and differ entiation of sympathetic as well as sensory neurons responsive to temperatur e and pain, while BDNF/TrkB, NT-4/TrkB and NT-3/TrkC signaling supports thos e of sensory neurons responsive to tactile stimuli, motor neurons, and senso ry neurons responsive to limb movement and position (Snider, Klein), respect ively. Thus, the neural development and maintenance of the neural network a re spatiotemporally controlled by neurotrophin signaling with or without som e redundancy in both peripheral and central nervous systems. Furthermore, T rk is also involved in human cancers as an oncogene or a proto-oncogene.

Trk as an oncogene
The Trk onocogene was one of the first transforming genes identified in hum an cancers [7]. The first Trk oncogene isolated from colon carcinoma was a fusion with the tropomyosin gene in the extracellular domain of the TrkA gen e which rendered constitutive activation in the tyrosine kinase activity. T he similar oncogenic rearrangement of the TrkA gene was found in thyroid pap illary carcinomas with higher frequency [8] as well as in acute myeloid leuk emia [9]. The systematic analysis done by Arevalo et al. [10] has suggested that alteration of the immunoglobulin-like NGF binding region of the extrace llular domain causes constitutive phosphorylation and spontaneous dimerizati on of the TrkA receptor, inducing malignant transformation of the cells. Re cently, a fusion of ETV6 to TrkC with constitutive activation of the tyrosin e kinase activity has also been reported to take place in acute leukemia wit h t(12;15)(p13;q25) [11]. Thus, it is interesting to note that so far oncog enic Trks have been exclusively observed in human malignancies with non-neur onal origin (Table 1).

Proto-oncogene Trks functioning in cancers
In contrast to the Trk oncogenes with genomic DNA rearrangement or mutation which might directly contribute to tumorigenesis, the proto-oncogene Trk was also shown to play a role in regulating important biology of cancers especia lly with neuronal or neuroendocrine origin.

The first evidence was reported in neuroblastoma (NBL), one of the most comm on pediatric neoplasms, which possesses enigmatic biology in different subse t of the tumor. The high levels of prototype TrkA was expressed in NBLs wit h good prognosis which often showed spontaneous regression [12-15]. Such tu mors usually occur in patients under one year of age and their DNA ploidy is aneuploid. A limited amount of NGF may be supplied from the stromal cells s uch as schwannian cells and fibroblasts, that, like normal sympathetic neuro ns, at least partly regulates differentiation and programmed cell death of t he NBL cells [16]. On the other hand, TrkA expression is strongly down-regu lated in NBLs with aggressive behavior which usually have amplification of t he MYCN oncogene as well as allelic loss of the region of chromosome 1p36 [1 2, 13]. In contrast, another family member, TrkB, is preferentially express ed in aggressive NBLs together with its preferred ligands BDNF and NT-4/5 wh ich stimulate in an autocrine/paracrine manner, confering potency to invade and/or metastasize on the tumor cells [17, 18]. TrkC is expressed rather in favorable NBLs at variable levels [19], but its preferred ligand, NT-3, is n early undetectable by RT-PCR in primary NBLs [16]. These suggest that, in r egressing NBLs, tumor cells expressing TrkA receptor are dependent on a limi ted amount of NGF supplied from the stromal cells, leading the tumor cells, which could obtain enough amount of NGF, to maturate otherwise they become t o die [16, 20]. This scenario is very similar to that observed in normally developing sympathetic neurons which survive and differentiate by the target -derived supplement of neurotrophins (a trophic theory). However, aggressiv e NBL cells shut off TrkA signals by down-regulating its expression and dist urbing the downstream signaling cascades, whereas they utilize BDNF or NT-4/ TrkB autocrine system to grow much efficiently. The recent report on the ex periment using a NBL cell line, SH-SY5Y (a line with a single copy of MYCN), transfected with TrkA or TrkB has demonstrated that the up-regulation of ins ulin-like growth factor-II (IGF-II) expression is a predominant feature of T rkA activation by NGF, and that IGF-II is a component of the effector mechan ism of TrkA activation by NGF in the TrkA-transfected cells [21]. This shou ld be tested in the primary NBL cells with high levels of endogenous TrkA ex pression because NBL cell lines and the favorable NBL cells have fundamental differences in biology and genetic background.

The other neurotrophic factors and their receptors are also functioning in N BL. The glial cell line-derive neurotrophic factor (GDNF) family of neurotr ophic factors, which include GDNF, artemin and neurturin, secreted from the NBL cells and the stromal cells activate their receptor complex composed of the Ret tyrosine kinase and the GFR_ co-receptors expressed in NBL cells [22 ]. However, GDNF/Ret/GFR_ autocrine system is functioning in both favorable and unfavorable NBLs to enhance tumor cells survival and differentiation [22 ]. Overall, many lines of evidence accumulated in the last decade suggest t hat, like normal sympathetic neurons, NBLs express neurotrophins and their r eceptors, if not the same, similarly to the sympathetic progenitor cells. N evertheless, the only major difference between NBL and sympathetic neuron is that expression of TrkA is strongly down-regulated and its downstream signal ing is largely impaired in most of the NBL cells with aggressive behavior. We need to know more about the molecular and biological characteristics of t he progenitors of the adrenal medullary chromaffin cells, from which most of the poor-prognostic NBLs originate.

Medulloblastoma (MBL) is the other neurogenic neoplasm, in which Trk recept ors may play a role in regulating the growth. In contrast to NBL, TrkB and TrkC, but not TrkA, are important for survival and differentiation of the MB L cells. The abundance of TrkC expression correlates with a better response to therapy in pediatric patients with MBL [23]. In some MBL cell lines, how ever, overexpression of TrkA induces apoptosis through Ras-mediated intracel lular signaling [24].

Although the rearranged TrkA gene is oncogenic in papillary thyroid carcino mas (PTCs), the prototype Trk family receptor genes participate in developme nt and progression of medullary thyroid carcinoma (MTC). In C cell hyperpla sia, the affected cells consistently express TrkB, with variable expression of TrkA and TrkC [25]. In later stages of MTC tumors, TrkB expression is su bstantially reduced, while TrkC expression is increased. Introduction of Tr kB into the MTC cell line resulted in impaired tumorigenesis and was associa ted with down-regulation of vascular endothelial growth factor (an angiogene sis factor) expression [25], suggesting that switching from TrkB to TrkC exp ression is necessary for the tumor progression. The other intriguing function of the prototype TrkA receptor has recently b een reported. Tagliabue et al. have found that in breast cancer cells expre ssing low levels of TrkA, NGF binding to the TrkA receptor stimulates p185HE R2 signaling to induce cell growth probably by recruiting and activating the p185HER2 receptors [26].

Trk signaling in cancer cells
The Trk receptors are abnormal not only in their structure or expression le vels but also in their intracellular signaling in cancerous cells. Most of the studies about Trk signaling have been performed using PC12 rat pheochrom ocytoma cell line which responds to NGF by inducing differentiation and grow th arrest. The recent reports suggest that differentiation signals by NGF o f the PC12 cells may be mediated through tyrosine phosphorylation of the Trk receptor and subsequent activation of Shc/Grb2/SOS, Ras, Raf, MEK and ERKs, while the survival signals in the same cells may be done through direct acti vation of PI3-kinase which in turn activates the downstream molecules such a s Akt and Bad [27]. On the other hand, in sympathetic neurons, activation o f PI3-kinase is not mediated by the tyrosine phosphorylation of the receptor but the Ras activation which promotes neuronal survival. These suggest that the Trk intracellular signaling pathway might be deregulated in cancer cells . This is also the case in neuroblastoma. In NBL cell lines with single co py of MYCN, NGF can induce differentiation when exogenous TrkA is overexpres sed [28]. However, in NBL cells with MYCN amplification, the NGF-stimulated TrkA receptors which were overexpressed cannot normally activate the downstr eam signaling molecules, resulting in no responsiveness of the cells to the ligand. Nevertheless, it is surprising that BDNF/TrkB signaling appears to be functioning in the same cells by promoting survival [22], though the sign aling pathway might be different from that of the sympathetic neurons [27]. Thus, the intracellular signal transduction system may also be deregulated i n cancer cells, that remains to be further pursued.

Trk signals meet with p53 and p73
The neurotrophin signaling through the Trk receptor activation can be segre gated into three intracellular signaling pathways: inhibition of programmed cell death (PCD, apoptosis), induction of growth arrest and promotion of neu ritogenesis. The recent lines of evidence have suggested that both p53 tumo r suppressor protein and its related protein p73 are involved in the inducti on of PCD and growth arrest in neuronal cells [29]. p73 is a recently ident ified candidate tumor suppressor whose gene is mapped to chromosome 1p36.2, a frequently deleted region in many human cancers including NBL and oligoden droglioma [30]. In cultured neonatal sympathetic neurons, p53 protein level s are increased in response to NGF withdrawal as well as p75NTR activation, and it functions downstream of c-Jun NH2-terminal kinase (JNK) and upstream of Bax to induce apoptosis [31] (Fig. 2). Actually, in p53-/- mice, natural ly occurring sympathetic neuron death is inhibited. Pozniak et al. have als o reported that p73 is primarily present in developing neurons as an NH2-ter minally truncated isoform (deltaNp73) whose levels are decreased when sympat hetic neurons undergo apoptosis after NGF withdrawal [29]. At that time, p5 3 becomes activated to be pro-apoptotic. In contrast to the truncated form of p73, full-length p73 has induced neuronal differentiation in a mouse NBL cell line N1E115 [32]. These suggest that the neuronal apoptosis induced by NGF withdrawal is at least partly regulated by a reciprocal balance between levels of pro-apoptotic p53 and anti-apoptotic deltaNp73. The involvement o f p53 in the Trk signaling has also been shown by the evidence that p53 is a ssociated with TrkA via the proto-oncogene product c-Abl as an adaptor or br idging molecule [33] and that activation of Ras by NGF stimulation of the Tr kA receptor induces p53 nuclear translocation and growth arrest in PC12 cell s [34] (Fig. 3). Furthermore, c-Ha-Ras gene could be a target of p53, and t he protein products induce a positive feedback loop by activating p14ARF tha t counteracts the negative feedback loop mediated by Mdm2 [35]. These obser vations strongly suggest that tumor suppressors, p53 and p73, function in th e neurotrophin signaling and modulate neuronal growth, differentiation and a poptosis.

In the cells of NBL and some other human cancers, wild type p53 is often lo calized in the cytoplasm [36]. Although the regulatory mechanism of cellula r localization of p53 and p73 is still unclear, a recent report suggests tha t activated Ras in the NGF/TrkA signaling stimulates nuclear translocation o f p53 and leads to the growth arrest by induction of p21WAF1 in PC12 cells [ 34]. The further important clues to understanding cell cycle regulation rel ated to the Trk activation have been suggested by some recent reports [37]. MYCN oncoproteins, which may down-regulate TrkA expression in NBL, induce ex pression of the Id-2 gene encoding a helix-loop-helix protein which in turn negatively regulates Rb tumor suppressor [38] (Fig. 3). Rb interacts with M dm2, which inhibits p53, as well as E2F1 which induces p73 [39]. On the oth er hand, the Ras pathway has been shown to have some interaction with Rb, Md m2 and/or p14ARF differently in different cellular responses [35]. For exam ple, the NGF/TrkA differentiation signal stimulates p14ARF through the Ras a ctivation which enhances nuclear translocation of the cytoplasmic p53 [34]. In addition, one of the growth signals from the activated protein tyrosine k inase receptor may be induction of Mdm2 by Ras [40]. Thus, the regulatory m echanism of the molecular interactions seems to be still complex, but it is obvious that the Trk signaling has met with p53 and p73 in neuronal cells.

Future directions
In this short review, I discussed about the role of Trk receptor signaling in both normal neurons and cancer cells. The distance between the cell memb rane, where Trk receptor tyrosine kinase locates, and the nucleus, where man y transcription factor complexes are functioning, is not so far as we imagin ed some years ago. In the future, we further need to know what regulates or even developmentally programs the timing of expression of Trks in vivo, how the Trk signals control neuritogenesis and cell survival, and how the Trk ac tivation regulates the cell cycle. The understanding of the cross-talk betw een Trks and other receptors signaling is also important. We also need to k now why the rearrangement of the Trk genes in cancer cells has occurred line age-specifically. The studies about aberrations of the Trk function in canc ers may give an important insight into better understanding its physiologica l role and contribute to develop new therapeutic strategies against aggressi ve tumors that kill the patient.

Acknowledgements
The author would like to thank Toshinori Ozaki, Masato Takahashi and Shiger u Sakiyama for critical reading of the manuscript.

References
1. R. Levi-Montalcini, The nerve growth factor 35 years later, Science 23 7 (1987) 1154-1162.
2. R. Klein, S.Q. Jing, V. Nanduri, E. O'Rourke, M. Barbacid, The trk prot o-oncogene encodes a receptor for nerve growth factor, Cell 65 (1991) 189-197.
3. B.L. Hempstead, D. Martin-Zanca, D.R. Kaplan, L.F. Parada, M.V. Chao, Hi gh-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor, Nature 350 (1991) 678-683.
4. M.V. Chao, M.A. Bothwell, A.H. Ross, H. Koprowski, A.A. Lanahan, C.R. Bu ck, A. Sehgal, Gene transfer and molecular cloning of the human NGF recepto r, Science 232 (1986) 518-521.
5. W.D. Snider, Functions of the neurotrophins during nervous system devel opment: What the knockouts are teaching us, Cell 77 (1994) 627-638.
6. R. Klein, Role of neurotrophins in mouse neuronal development, FASEB J . 8 (1994) 738-744.
7. M. Barbacid, F. Lamballe, D. Pulido, R. Klein, The trk family of tyrosi ne protein kinase receptors, Biochim. Biophys. Acta 1072 (1991) 115-27.
8. M. Eguchi, M. Eguchi-Ishimae, A. Tojo, K .Morishita, K. Suzuki, Y. Sato, S. Kudoh, K. Tanaka, M. Setoyama, F. Nagamura, S. Asano, N. Kamada, Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12; 15)(p13;q25), Blood 93 (1999) 1355-1363.
9. G.W. Reuther, Q.T. Lambert, M.A. Caligiuri, C.J. Der, Identification an d characterization of an activating TrkA deletion mutation in acute myeloid leukemia, Mol. Cell Biol. 20 (2000) 8655-8666.
10. J.C. Arevalo, B. Conde, B.L. Hempstead, M.V. Chao, D. Martin-Zanca, P. Perez, TrkA immunoglobulin-like ligand binding domains inhibit spontaneous activation of the receptor, Mol. Cell Biol. 20 (2000) 5908-5916.
11. M. Eguchi, M. Eguchi-Ishimae, A. Tojo, K. Morishita, K. Suzuki, Y. Sato , S. Kudoh, K. Tanaka, M. Setoyama, F. Nagamura, S. Asano, N. Kamada, Fusio n of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(1 2;15)(p13;q25), Blood 93 (1999) 1355-1363.
12. A. Nakagawara, M. Arima, C.G. Azar, N.J. Scavarda, G.M. Brodeur, Inver se relationship between trk expression and N-myc amplification in human neur oblastomas, Cancer Res. 52 (1992) 1364-1368.
13. A. Nakagawara, M. Arima-Nakagawara, N.J. Scavarda, C.G. Azar, A.B. Cant or, G.M. Brodeur, Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma, N. Engl. J. Med. 328 (19 93) 847-854.
14. T. Suzuki, E. Bogenmann, H. Shimada, D. Stram, R.C. Seeger, Lack of hi gh-affinity nerve growth factor receptors in aggressive neuroblastomas, J. Natl. Cancer Inst. 85 (1993) 377-384.
15. P. Kogner, G. Barbany, C. Dominici, M.A. Castello, G. Raschella, H. Per sson, Coexpression of messenger RNA for TRK protooncogene and low affinity nerve growth factor receptor in neuroblastoma with favorable prognosis, Can cer Res. 53 (1993) 2044-2050.
16. A. Nakagawara, The NGF Story and Neuroblastoma, Med. Pediatr. Oncol. 31 (1998) 113-115.
17. A. Nakagawara, C.G. Azar, N.J. Scavarda, G. M. Brodeur, Expression and function of TRK-B and BDNF in human neuroblastomas, Mol. Cell. Biol. 14 (19 94) 759-767.
18. K. Matsumoto, R.K. Wada, J.M. Yamashiro, D.R. Kaplan, C.J. Thiele, Exp ression of brain-derived neurotrophic factor and p145TrkB affects survival, differentiation, and invasiveness of human neuroblastoma cells, Cancer Res. 55 (1995) 1798-1806.
19. D. Yamashiro, A. Nakagawara, N. Ikegaki, X. Liu, G.M. Brodeur, Express ion of TRK-C in favorable human neuroblastomas, Oncogene 12 (1996) 37-41.
20. A. Nakagawara, Molecular basis of spontaneous regression of neuroblasto ma: Role of neurotrophic signals and genetic abnormalities, Human Cell 11 ( 1998) 115-124.
21. C.J. Kim, T. Matsuo, H.Lee K, C.J. Thiele, Up-regulation of insulin-li ke growth factor-II expression is a feature of TrkA but not TrkB activation in SH-SY5Y neuroblastoma, Am. J. Pathol. 155 (1999) 1661-1670.
22. T. Hishiki, Y. Nimura, E. Isogai, K. Kondo, S. Ichimiya, Y. Nakamura, T . Ozaki, S. Sakiyama, M. Hirose, N. Seki, H. Takahashi, N. Ohnuma, M. Tanabe , A. Nakagawara, Glial cell line-derived neurotrophic factor/neurturin-indu ced differentiation and its enhancement by retinoic acid in primary human ne uroblastomas expressing c-Ret, GFR_-1 and GFR_-2, Cancer Res. 58 (1998) 215 8-2165.
23. R.A. Segal, L.C. Goumnerova, Y.K. Kwon, C.D. Stiles, S.L. Pomeroy, Exp ression of the neurotrophin receptor TrkC is linked to a favorable outcome i n medulloblastoma, Proc. Natl. Acad. Sci. U.S.A. 91 (1994) 12867-12871.
24. T.T. Chou, J.Q. Trojanowski, V.M. Lee, A novel apoptotic pathway induc ed by nerve growth factor-mediated TrkA activation in medulloblastoma, J. B iol. Chem. 275 (2000) 565-570.
25. L.M. McGregor, B.K. McCune, J.R. Graff, P.R. McDowell, K.E. Romans, G.D . Yancopoulos, D.W. Ball, S.B. Baylin, B.D. Nelkin, Roles of trk family neu rotrophin receptors in medullary thyroid carcinoma development and progressi on, Proc. Natl. Acad. Sci. U.S.A. 96 (1999) 4540-4545.
26. E. Tagliabue, F. Castiglioni, C. Ghirelli, M. Modugno, L. Asnaghi, G. S omenzi, C. Melani, S. Menard, Nerve growth factor cooperates with p185HER2 in activating growth of human breast carcinoma cells, J. Biol. Chem. 25 (20 00) 5388-5394.
27. L.J. Klesse, L.F. Parada, Trks: Signal transduction and intracellular pathways, Microsc. Res. Tech. 45 (1999) 210-216.
28. A. Eggert, N. Ikegaki, X. Liu, T.T. Chou, V.M. Lee, J.Q. Trojanowski, G .M. Brodeur, Molecular dissection of TrkA signal transduction pathways medi ating differentiation in human neuroblastoma cells, Oncogene 19 (2000) 2043 -2051.
29. C.D. Pozniak, S. Radinovic, A. Yang, F. McKeon, D.R. Kaplan, F.D. Mille r, An anti-apoptotic role for the p53 family member, p73, during developmen tal neuron death, Science 289 (2000) 304-306.
30. S. Ichimiya, Y. Nimura, H. Kageyama, N. Takada, M. Sunahara, T. Shishik ura, Y. Nakamura, S. Sakiyama, N. Seki, M. Ohira, Y. Kaneko, F. McKeon, D. C aput, A. Nakagawara, p73 at chromosome 1p36.3 is lost in advanced stage neu roblastoma but its mutation is infrequent, Oncogene 18 (1999) 1061-1066.
31. R.S. Aloyz, S.X. Bamji, C.D. Pozniak, J.G. Toma, J. Atwal, D.R. Kaplan, F.D. Miller, p53 is essential for developmental neuron death as regulated b y the TrkA and p75 neurotrophin receptors, J. Cell Biol. 143 (1998) 1691-1703.
32. V. De Laurenzi, G. Raschella, D. Barcaroli, M .Annicchiarico-Petruzzell i, M. Ranalli, M.V. Catani, B. Tanno, A. Costanzo, M. Levrero, G. Melino, I nduction of neuronal differentiation by p73 in a neuroblastoma cell line, J . Biol. Chem 275 (2000) 15226-15231.
33. H. Yano, F. Cong, R.B. Birge, S.P. Goff, M.V. Chao, Association of the Abl tyrosine kinase with the Trk nerve growth factor receptor, J. Neurosci. Res. 59 (2000) 356-364.
34. A.L. Hughes, L. Gollapudi, T.L. Sladek, K.E. Neet, Mediation of nerve growth factor-driven cell cycle arrest in PC12 cells by p53 - Simultaneous d ifferentiation and proliferation subsequent to p53 functional inactivation, J. Biol. Chem. 275 (2000) 37829-37837.
35. V. Deguin-Chambon, M. Vacher, M. Jullien, E. May, J.C. Bourdon, Direct transactivation of c-Ha-Ras gene by p53: evidence for its involvement in p53 transactivation activity and p53-mediated apoptosis, Oncogene 19 (2000) 583 1-5841.
36. U.M. Moll, M. LaQuaglia, J. Benard, G. Riou, Wild-type p53 protein und ergoes cytoplasmic sequestration in undifferentiated neuroblastomas but not in differentiated tumors, Proc. Natl. Acad. Sci. U.S.A. 92 (1995) 4407-4411.
37. J.L. Urdiales, E. Becker, M. Andrieu, A. Thomas, J. Jullien, L.A. van G runsven, S. Menut, G.I. Evan, D. Martin-Zanca, B.B. Rudkin, Cell cycle phas e-specific surface expression of nerve growth factor receptors TrkA and p75N TR, J. Neurosci. 18 (1998) 6767-6775.
38. A. Lasorella, M. Noseda, M. Beyna, A. Iavarone, Id2 is a retinoblastom a protein target and mediates signalling by Myc oncoproteins, Nature 407 (2 000) 592-598.
39. B. Vogelstein, D. Lane, A.J. Levine, Surfing the p53 network, Nature 4 08 (2000) 307-310.
40. S. Ries, C. Biederer, D. Woods, O. Shifman, S. Shirasawa, T. Sasazuki, M . McMahon, M. Oren, F. McCormick, Opposing effects of Ras on p53: transcrip tional activation of mdm2 and induction of p19ARF, Cell 103 (2000) 321-330.

Figure 1. The structure of neurotrophin family receptors. (A) Trks and p75NTR are high-affinity and low-affinity receptors for their cognate ligands, respectively. The neuronal form of TrkA receptor has a sho rt insertion in the juxtamembrane region of its extracellular domain. Both TrkB and TrkC have truncated isoforms without the kinase domain. p75NTR str ucturally belongs to the tumor necrosis factor receptor or Fas family of dea th receptor. (B) Neurotrophins and their preferred high-affinity receptors

Figure 2. Model of apoptotic pathway of sympathetic neurons induced by NGF w ithdrawal or p75NTR activation. DeltaNp73 is a splicing variant of the p73 candidate tumor suppressor. A part of this scheme has been referred from Re f. 31.

Figure 3. A possible regulatory pathway of growth, differentiation and apopt osis in neuroblastoma or neuronal cells.

Table 1. The oncogene Trks are activated in non-neuronal malignancies, whil e the proto-oncogene Trks function in the tumors with neuronal origin.
Nomenclatures: TrkA/NTRK1, TrkB/NTRK2 and TrkC/NTRK3.

Back . . .