N Hu

Publications (5)66.94 Total impact

• Source

  Available from: aacrjournals.org

  Article: Retinoblastoma gene deficiency has mitogenic but not tumorigenic effects on erythropoiesis.

  N Hu, M L Gulley, J T Kung, E Y Lee
  [show abstract] [hide abstract]
  ABSTRACT: The retinoblastoma protein (Rb), an important ubiquitous cell cycle regulator, was initially identified as the retinoblastoma tumor suppressor. To further address the activities of Rb in proliferation and tumorigenesis in the hematopoietic lineage, we transplanted Rb-/- fetal liver cells into sibling mice and assessed the outcome of Rb-/- hematopoietic cells in both short-term and long-term studies. Rb-/- hematopoietic cells rescued lethally irradiated mice with an efficiency comparable to that of wild-type cells. In spleen colony-forming unit assays, proliferation rates of the Rb-/- cells were greater than those of the wild-type cells. Similarly, in vitro burst-forming unit-erythroid and colony-forming unit-erythroid assays showed increased erythroid colony numbers from Rb-/- embryonic livers. Recipients of Rb-/- cells lived for more than 15-18 months, and most blood cell lineages matured normally with the expected switch from fetal to adult hemoglobin. However, the continued presence of nucleated erythrocytes in the peripheral blood and extensive extramedullary erythropoiesis indicated that the Rb-/- erythrocytes were not completely normal. No erythroleukemia developed during the 15-18 month period following transplantation. These results demonstrate the mitogenic effect but not tumorigenic transformation in erythrocyte lineage in the absence of Rb, which is distinct from the effect of Rb deficiency in neuroectodermal cells. The study supports the prevalent model that loss of the ubiquitously expressed tumor suppressor gene predisposes to only a limited spectrum of tumors.
  Cancer Research 10/1997; 57(18):4123-9. · 7.86 Impact Factor
• Article: Molecular cloning and developmental expression of mouse p130, a member of the retinoblastoma gene family.

  G Chen, C T Guy, H W Chen, N Hu, E Y Lee, W H Lee
  [show abstract] [hide abstract]
  ABSTRACT: With sequence homology to the SV40 T antigen-binding domain of the retinoblastoma protein (Rb), p107 and p130 constitute two additional members of the Rb family. To explore the potential function of p130 in mouse development, we cloned the full-length mouse cDNA for p130 and characterized p130 mRNA expression in mice. The deduced mouse p130 protein sequence shares a higher degree of similarity with mouse p107 than with mouse Rb. In adult mice, p130 mRNA is found in all tissues examined. Levels of p130 mRNA vary among different adult tissues, with the highest level in testis. Within testis, p130 mRNA is found predominantly in Leydig cells. Additionally, p130 expression in testis correlates with sexual maturation, suggesting p130 is important for the development of testis and, in particular, Leydig cells. In situ hybridization shows that in post coitus day 12.5 and 14.5 mouse embryos, distribution of p130 mRNA is quite uniform with the exception of a few tissues. Little differences in mRNA levels of either p130 or p107 were found between normal and Rb-deficient embryos, suggesting that p130 and p107 are expressed independently of Rb. Our data are consistent with the hypothesis that p130 and p107 do not compensate for the loss of Rb and support the view that p130 is related to, yet distinct from, the RB gene.
  Journal of Biological Chemistry 05/1996; 271(16):9567-72. · 4.77 Impact Factor
• Article: Dual roles of the retinoblastoma protein in cell cycle regulation and neuron differentiation.

  E Y Lee, N Hu, S S Yuan, L A Cox, A Bradley, W H Lee, K Herrup
  [show abstract] [hide abstract]
  ABSTRACT: To assess the functions of the retinoblastoma protein (RB) during normal development, we have analyzed mouse embryos that lack a functional copy of the retinoblastoma gene (genotype: Rb-1 delta 20/Rb-1 delta 20). Our findings demonstrate that RB plays an important role in the regulation of the neuronal cell cycle. In mutant embryos, dividing cells are found well outside of the normal neurogenic regions in both the central and peripheral nervous systems. In addition to abnormal cell cycle regulation, however, the mutant embryos show two less expected phenotypes. First, many of the ectopically dividing cells die by apoptosis shortly after their entrance into S phase. In sensory ganglia, most nerve cells die by this process, beginning at about the same time as normal target-related neuronal death. Second, although the expression of certain differentiation markers such as N-CAM and Brn-3.0 appears to be near normal, nerve cells, especially in sensory ganglia, do not mature properly. Their morphology is stunted and expression of neuronal beta II tubulin is greatly reduced. Preferential reduction in the expression of TrkA, TrkB, and the low-affinity neurotrophin receptor p75LNGFR may be relevant to neuronal cell death and lack of neuronal differentiation seen in the mutant embryos. Primary cultures of dorsal root and trigeminal ganglion cells from later stage mutant embryos reveal a decrease in neuronal cell survival and in neurite outgrowth even in the presence of the appropriate neurotrophins. Taken together, these results suggest that the p110RB protein not only regulates progression through the cell cycle but is also important for cell survival and differentiation.
  Genes & Development 10/1994; 8(17):2008-21. · 11.66 Impact Factor
• Article: Heterozygous Rb-1 delta 20/+mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance.

  N Hu, A Gutsmann, D C Herbert, A Bradley, W H Lee, E Y Lee
  [show abstract] [hide abstract]
  ABSTRACT: Humans with a germline mutation of the RB gene are predisposed to retinoblastoma with a 90% penetrance and are at higher risk for other rare tumors. We have established a mouse strain carrying a germ-line mutation of the Rb-1 gene. Here we describe a nearly 100% incidence of spontaneous pituitary tumors which arise in Rb-1 heterozygous mice from ages 2 to 11 months. Histological and immunological analysis indicate that these tumors originate from the intermediate lobe of the pituitary gland, which is a vestigial structure in adult humans. Progression of the tumors can be followed by the elevated level of a specific proteolytic product of pro-opiomelanocortin prohormone, alpha-melanocyte stimulating hormone, in the circulating blood of the tumor-bearing animals. Multiple foci are frequently seen in the tiny intermediate lobe of the pituitary gland which contains approximately 1.5 x 10(5) cells. The tumor tissues invariably lose expression of full-length Rb protein due to loss of the single wild-type Rb-1 allele. The Rb knock out mouse strain provides a unique model for addressing tissue-specific tumor predisposition by inactivation of a ubiquitously expressed tumor suppressor gene.
  Oncogene 05/1994; 9(4):1021-7. · 6.37 Impact Factor
• Article: Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis.

  E Y Lee, C Y Chang, N Hu, Y C Wang, C C Lai, K Herrup, W H Lee, A Bradley
  [show abstract] [hide abstract]
  ABSTRACT: The retinoblastoma gene, a prototypic tumour-suppressor gene, encodes a nuclear phosphoprotein (Rb). To understand better the role of Rb in development and in tumorigenesis, mice with an insertional mutation in exon 20 of the Rb-1 locus were generated. Homozygous mutants die before the 16th embryonic day with multiple defects. The haematopoietic system is abnormal; there is a significant increase in the number of immature nucleated erythrocytes. In the nervous system, ectopic mitoses and massive cell death are found, particularly in the hindbrain. All spinal ganglion cells die, but the neural retina is unaffected. Transfer of the human retinoblastoma (RB) mini-transgene into the mutant mice corrects the developmental defects. Thus, Rb is essential for normal mouse development.
  Nature 10/1992; 359(6393):288-94. · 36.28 Impact Factor