Alternative titles; symbols
HGNC Approved Gene Symbol: PTN
Cytogenetic location: 7q33 Genomic coordinates (GRCh38): 7:137,227,341-137,343,733 (from NCBI)
Li et al. (1990) found that a heparin-binding mitogenic protein isolated from bovine uterus shared N-terminal sequence with a protein isolated from newborn rat brain. The cDNAs of the bovine, human, and rat genes were, furthermore, found to encode extraordinarily conserved proteins unrelated to known growth or neurotrophic factors, although identity of nearly 50% was found with the predicted sequence of a retinoic acid-induced transcript in differentiating mouse embryonal carcinoma cells. RNA transcripts encoding this protein were widely distributed in tissues and were developmentally regulated. This protein, previously designated heparin-binding growth factor-8, was renamed pleiotrophin (PTN) to reflect its diverse activities (see GENE FUNCTION). Li et al. (1990) suggested that PTN is the first member of a family of developmentally regulated cytokines.
Eddy et al. (1991) noted that expression of PTN is developmentally regulated, increasing in the brain during embryogenesis and reaching its maximum expression at the time of birth. The gene codes for a 168-residue protein that is a precursor for a previously described brain-derived heparin-binding protein of 136 amino acids.
Li et al. (1990) found that lysates of COS-7 cells transiently expressing PTN were mitogenic for NRK cells and initiated neurite outgrowth from mixed cultures of embryonic rat brain cells.
Zhang et al. (1999) found that a mutant PTN that contained only the first N-terminal 40 amino acids was a dominant negative, because its expression effectively blocked transformation of NIH 3T3 cells by wildtype PTN and formed disulfide-linked heterodimers with wildtype PTN when expressed in human breast cancer cells that expressed high levels of endogenous PTN. Furthermore, the truncated PTN effectively reversed the malignant phenotype of these cells, indicating that it functionally blocks endogenous PTN signaling and that endogenous PTN signaling is required to maintain the malignant phenotype of these particular cells. Zhang et al. (1999) used homologous recombination to introduce the dominant-negative PTN mutant into embryonic stem cells to generate chimeric mice. All highly chimeric male mice with germinal epithelium exclusively derived from embryonic stem cells with the heterologous PTN mutation were sterile. Their testes were uniformly atrophic, and the spermatocytes were strikingly apoptotic at all stages of development. The results supported a central role of PTN signaling in normal spermatogenesis and suggested that interruption of PTN signaling may lead to sterility in males.
Souttou et al. (1998) found that PTN is frequently expressed in gastrointestinal cancer and particularly in pancreatic cancer. Weber et al. (2000) used ribozymes to deplete PTN mRNA from a pancreatic cancer cell line and studied the resulting phenotype. The reduction of PTN resulted in a decrease in the proliferation rate, soft agar colony formation, and tumor growth in animals. The autocrine function of PTN was confirmed by using PTN-binding antibodies that inhibited the proliferation rate by 50% in this cell line and also in a different pancreatic cancer cell line. The study identified PTN as a new and essential growth factor for pancreatic cancer. Due to the restricted expression pattern of PTN in adults, PTN was suggested as a target for pancreatic cancer therapy.
Using cDNA microarray analysis, Mi et al. (2007) found that Ptn mRNA was upregulated in acutely denervated rat Schwann cells from sciatic nerve. High levels of Ptn mRNA peaked at day 7 but were not maintained, returning to baseline levels by 3 months. In a spinal cord explant system, Ptn caused increased outgrowth of spinal motor axons and protected spinal motor neurons against chronic excitotoxic injury. In neonatal mice, Ptn protected facial motor neurons against cell death induced by deprivation of growth factors. In adult rats, Ptn enhanced regeneration of myelinated axons across a graft in transected sciatic nerve. Further studies suggested that Alk (105590) may mediate trophic activities of Ptn. The findings indicated that Ptn has a neurotrophic role in peripheral nerves.
Himburg et al. (2010) found that pleiotrophin induced expansion of human and mouse hematopoietic stem cells (HSCs) in culture. Systemic administration of pleiotrophin to irradiated mice caused expansion of bone marrow stem and progenitor cells. Pleiotrophin activated phosphoinositide 3-kinase (PI3K; see 601232) signaling in HSCs, and antagonism of PI3K or Notch (see 190198) signaling inhibited pleiotrophin-mediated expansion of HSCs in culture. Himburg et al. (2010) concluded that pleiotrophin is a regulator of HSC expansion and regeneration.
Lau et al. (2012) performed transcriptional profiling of macrodactyly tissue from 4 pediatric patients with isolated nonsyndromic macrodactyly (155500). Analysis of these data identified 7,295 differentially expressed genes in macrodactyly compared to adult normal abdominal subcutaneous adipose tissue (SAT). The candidate genes overexpressed in macrodactyly tissue included several well-characterized mitogens (e.g., BMP5, 112265, BMP7, 112267, TGFB3, 190230, and WNT2, 147870), but the mitogen with the highest fold-change overexpression was pleiotrophin (PTN; 162095). At the transcriptional level, qPCR confirmed PTN overexpression in macrodactyly compared to adult abdominal SAT. PTN was overexpressed in all macrodactyly samples, but the degree of overexpression varied greatly among patients. There were insufficient samples to correlate PTN overexpression levels with clinical phenotype.
Milner et al. (1992) found that the PTN gene is arranged in 5 exons in a fashion similar to that of the mouse midkine (MK) gene, which is a member of the same family of developmentally regulated cytokines. Li et al. (1992) isolated genomic clones of the PTN gene, characterized its promoter region, determined its transcription initiation site(s), and established functional activity of the PTN promoter. Lai et al. (1992) found that the PTN gene spans more than 65 kb and contains at least 7 exons. The open reading frame (ORF) is located on 4 exons. The splice sites in the ORF coincide with the boundaries of functional domains in the human PTN protein and appear to be conserved in the mouse PTN.
Eddy et al. (1991) used a cDNA for Southern blot analysis of human/mouse somatic cell hybrids and found that the PTN gene segregated with chromosome 7. Using cell hybrids retaining chromosome 7 rearrangements, they mapped the PTN gene to 7q22-qter. By fluorescence in situ hybridization (FISH), Milner et al. (1992) localized the PTN gene to 7q33-q34. By FISH, Li et al. (1992) mapped the gene to 7q33. By linkage studies in interspecific backcross progeny, they demonstrated that the homologous mouse gene, Ptn, is on chromosome 6. O'Hara et al. (1995) mapped the PTN gene to 7q22-qter using somatic cell hybrid analysis.
Eddy, R. L., Kretschmer, P. J., Fairhurst, J. L., Shows, T. B., Bohlen, P., O'Hara, B., Kovesdi, I. A human gene family of neurite outgrowth-promoting proteins: the gene for a heparin binding neurite outgrowth-promoting factor maps to 7q22-qter. (Abstract) Cytogenet. Cell Genet. 58: 1920 only, 1991.
Himburg, H. A., Muramoto, G. G., Daher, P., Meadows, S. K., Russell, J. L., Doan, P., Chi, J.-T., Salter, A. B., Lento, W. E., Reya, T., Chao, N. J., Chute, J. P. Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nature Med. 16: 475-482, 2010. [PubMed: 20305662] [Full Text: https://doi.org/10.1038/nm.2119]
Lai, S., Czubayko, F., Riegel, A. T., Wellstein, A. Structure of the human heparin-binding growth factor gene pleiotrophin. Biochem. Biophys. Res. Commun. 187: 1113-1122, 1992. [PubMed: 1530608] [Full Text: https://doi.org/10.1016/0006-291x(92)91312-e]
Lau, F. H., Xia, F., Kaplan, A., Cerrato, F., Greene, A. K., Taghinia, A., Cowan, C. A., Labow, B. I. Expression analysis of macrodactyly identifies pleiotrophin upregulation. PLoS One 7: e40423, 2012. Note: Electronic Article. [PubMed: 22848377] [Full Text: https://doi.org/10.1371/journal.pone.0040423]
Li, Y.-S., Hoffman, R. M., Le Beau, M. M., Espinosa, R., III, Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Deuel, T. F. Characterization of the human pleiotrophin gene: promoter region and chromosomal localization. J. Biol. Chem. 267: 26011-26016, 1992. [PubMed: 1464612]
Li, Y.-S., Milner, P. G., Chauhan, A. K., Watson, M. A., Hoffman, R. M., Kodner, C. M., Milbrandt, J., Deuel, T. F. Cloning and expression of a developmentally regulated protein that induces mitogenic and neurite outgrowth activity. Science 250: 1690-1694, 1990. [PubMed: 2270483] [Full Text: https://doi.org/10.1126/science.2270483]
Mi, R., Chen, W., Hoke, A. Pleiotrophin is a neurotrophic factor for spinal motor neurons. Proc. Nat. Acad. Sci. 104: 4664-4669, 2007. [PubMed: 17360581] [Full Text: https://doi.org/10.1073/pnas.0603243104]
Milner, P. G., Shah, D., Veile, R., Donis-Keller, H., Kumar, B. V. Cloning, nucleotide sequence, and chromosome localization of the human pleiotrophin gene. Biochemistry 31: 12023-12028, 1992. [PubMed: 1457401] [Full Text: https://doi.org/10.1021/bi00163a009]
O'Hara, B., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Shows, T. B., Eddy, R. L., Bohlen, P., Kovesdi, I. Chromosomal assignment of the heparin-binding cytokine genes MDK and PTN in mouse and man. Cytogenet. Cell Genet. 69: 40-43, 1995. [PubMed: 7835084] [Full Text: https://doi.org/10.1159/000133934]
Souttou, B., Juhl, H., Hackenbruck, J., Rockseisen, M., Klomp, H. J., Raulais, D., Vigny, M., Wellstein, A. Relationship between serum concentrations of the growth factor pleiotrophin and pleiotrophin-positive tumors. J. Nat. Cancer Inst. 90: 1468-1473, 1998. [PubMed: 9776412] [Full Text: https://doi.org/10.1093/jnci/90.19.1468]
Weber, D., Klomp, H.-J., Czubayko, F., Wellstein, A., Juhl, H. Pleiotrophin can be rate-limiting for pancreatic cancer cell growth. Cancer Res. 60: 5284-5288, 2000. [PubMed: 11016659]
Zhang, N., Yeh, H.-J., Zhong, R., Li, Y.-S., Deuel, T. F. A dominant-negative pleiotrophin mutant introduced by homologous recombination leads to germ-cell apoptosis in male mice. Proc. Nat. Acad. Sci. 96: 6734-6738, 1999. [PubMed: 10359781] [Full Text: https://doi.org/10.1073/pnas.96.12.6734]