NPDC-1, a regulator of neural cell proliferation and differentiation, interacts with E2F-1, reduces its binding to DNA and modulates its transcriptional activity

We have previously identified NPDC-1, a neural factor involved in the control of proliferation and differentiation, and we have shown that the stable introduction of NPDC-1 into transformed cells down-regulates cell proliferation both by increasing the generation time and by suppressing transformed properties. The data presented here indicate that, in vitro, NPDC-1 is able to interact with the transcription factor E2F-1 and some cell cycle proteins, such as D-cyclins and cdk2. In addition, two-hybrid experiments in mammalian cells show that the interaction between NPDC-1 and E2F-1 can also occur in vivo. This interaction reduces the binding of E2F-1 to DNA and its transcriptional activity. Taken together, the data suggest that NPDC-1 could influence cell cycle progression and neural differentiation through its association with E2F-1.

[1]  E. Harlow,et al.  Antibodies: A Laboratory Manual , 1988 .

[2]  K. Yoshikawa,et al.  Necdin, A Postmitotic Neuron-specific Growth Suppressor, Interacts with Viral Transforming Proteins and Cellular Transcription Factor E2F1* , 1998, The Journal of Biological Chemistry.

[3]  K. Helin,et al.  Heterodimerization of the transcription factors E2F-1 and DP-1 leads to cooperative trans-activation. , 1993, Genes & development.

[4]  Marc Vidal,et al.  A cDNA encoding a pRB-binding protein with properties of the transcription factor E2F , 1992, Cell.

[5]  B. Dynlacht,et al.  Mechanism of transcriptional repression of E2F by the retinoblastoma tumor suppressor protein. , 1999, Molecular cell.

[6]  A. Berns,et al.  Requirement for a functional Rb-1 gene in murine development , 1992, Nature.

[7]  E. Dupont,et al.  Developmental pattern of expression of NPDC‐1 and its interaction with E2F‐1 suggest a role in the control of proliferation and differentiation of neural cells , 1998, Journal of neuroscience research.

[8]  K. Walsh,et al.  MyoD-induced expression of p21 inhibits cyclin-dependent kinase activity upon myocyte terminal differentiation , 1995, Molecular and cellular biology.

[9]  Keiji Tanaka,et al.  Transcriptional squelching by ectopic expression of E2F-1 and p53 is alleviated by proteasome inhibitors MG-132 and lactacystin , 1997, Oncogene.

[10]  T. Jacks,et al.  Tumor Induction and Tissue Atrophy in Mice Lacking E2F-1 , 1996, Cell.

[11]  A. Lassar,et al.  Inhibition of myogenic differentiation in proliferating myoblasts by cyclin D1-dependent kinase , 1995, Science.

[12]  S. Weintraub,et al.  Mechanism of active transcriptional repression by the retinoblastoma protein , 1995, Nature.

[13]  H. Okayama,et al.  High-efficiency transformation of mammalian cells by plasmid DNA. , 1987, Molecular and cellular biology.

[14]  J. Wang,et al.  Dual mechanisms for the inhibition of E2F binding to RB by cyclin-dependent kinase-mediated RB phosphorylation , 1997, Molecular and cellular biology.

[15]  N. Dyson,et al.  pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes. , 1997, Genes & development.

[16]  J. P. Mornon,et al.  MANSEK and SUNHCA. Two interactive programs for the hydrophobic cluster analysis of protein sequences , 1993, Comput. Appl. Biosci..

[17]  W. D. Cress,et al.  Subunit composition determines E2F DNA-binding site specificity , 1997, Molecular and cellular biology.

[18]  W. Gu,et al.  Reversal of terminal differentiation mediated by p107 in Rb-/- muscle cells. , 1994, Science.

[19]  J L Sussman,et al.  A 3D building blocks approach to analyzing and predicting structure of proteins , 1989, Proteins.

[20]  B. Gallie,et al.  Dual mechanisms of repression of E2F1 activity by the retinoblastoma gene product. , 1996, The EMBO journal.

[21]  A. Bradley,et al.  Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis , 1992, Nature.

[22]  R. Weinberg,et al.  Effects of an Rb mutation in the mouse , 1992, Nature.

[23]  G. Hannon,et al.  Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD , 1995, Science.

[24]  J. Gibrat,et al.  Secondary structure prediction: combination of three different methods. , 1988, Protein engineering.

[25]  J. Bartek,et al.  Induction of S-phase entry by E2F transcription factors depends on their nuclear localization , 1997, Molecular and cellular biology.

[26]  D. Livingston,et al.  Cyclin A-kinase regulation of E2F-1 DNA binding function underlies suppression of an S phase checkpoint , 1995, Cell.

[27]  J. Nevins,et al.  Expression of transcription factor E2F1 induces quiescent cells to enter S phase , 1993, Nature.

[28]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[29]  E. Dupont,et al.  Identification of a neural-specific cDNA, NPDC-1, able to down-regulate cell proliferation and to suppress transformation. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[30]  C. Peng,et al.  Cyclin A/CDK2 binds directly to E2F-1 and inhibits the DNA-binding activity of E2F-1/DP-1 by phosphorylation , 1994, Molecular and cellular biology.

[31]  A. Lassar,et al.  pRb is required for MEF2-dependent gene expression as well as cell-cycle arrest during skeletal muscle differentiation , 1999, Current Biology.

[32]  P. Y. Chou,et al.  Empirical predictions of protein conformation. , 1978, Annual review of biochemistry.

[33]  James M. Roberts,et al.  CDK inhibitors: positive and negative regulators of G1-phase progression. , 1999, Genes & development.