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PETER LENGYEL

Roles of the p200 family proteins in modulating mammalian differentiation, cell proliferation, and transcription.
The p200 family proteins were discovered as proteins inducible by the interferons. The interferons are cytokines with antimicrobial, immunomodulatory and cell growth regulatory activities, which also affect differentiation. The murine p200 family proteins are encoded by nine or more genes forming a cluster on chromosome 1. The cluster, which also exists in humans, arose by repeated gene duplications. Functionally, the best characterized murine p200 family proteins are p204 and p202.

p204 is expressed at a relatively high level in skeletal and cardiac muscle. This level increases during skeletal myoblast differentiation in consequence of transactivation by the muscle-specific MyoD protein. p204 is required for the fusion of myoblasts to myotubes in vitro. Its overexpression triggers this fusion even in growth medium. p204 elicits differentiation in part, by overcoming the inhibition of the transcriptional activity of the MyoD protein by the three Id (inhibitor of differentiation) proteins, i.e. Id1, Id2 and Id3. p204 binds, sequesters, and accelerates the degradation of the Id proteins. p204, whose distribution among the nucleoli, the nucleoplasm and the cytoplasm is regulated, also blocks ribosomal RNA synthesis by binding and inhibiting the binding to DNA of the UBF transcription factor.

The level of p202 (actually of two highly similar sister proteins, p202a and p202b) also increases during muscle differentiation in consequence of transcription of the gene(s) encoding p202 by MyoD. p202 may contribute to muscle differentiation, among others, by inhibiting cell proliferation while protecting the cells from apoptosis. p202 accomplishes this by binding and inhibiting the sequence-specific binding to DNA and thereby the activity of several transcription factors. These include, c-Fos, c-Jun, AP2, E2F1, E2F4, NF-kB, MyoD, myogenin and c-Myc. p202 also binds pRb and inhibits the activity of p53. In turn, the transcription of the genes encoding p202 is inhibited by p53. The inhibitory activity of p202 is overcome by the binding to p202 of the p53 binding protein 1, and also of the human adenovirus oncoprotein E1A. Overexpression of p202 was linked to susceptibility to the autoimmune disease lupus erythematosus. It is likely that p202 contributes to this disease by its antiapoptotic effect. This effect may be related to the inhibition by p202 of the activities of the proapoptotic transcription factors p53, E2F1 and c-Myc. c-Myc was shown to transactivate the expression of the inhibitor of differentiation protein Id2. Thus, by blocking c-Myc activity, p202 also lowers the level of Id2.

The presence of p202, p204 and several Id proteins in a variety of tissues, as well as other observations, suggest that p204, p202 and possibly other p200 family proteins, are also involved in modulating the differentiation of several tissues and organs, besides skeletal muscle. These problems, as well as the possible role of p200 family proteins in controlling malignancy are under investigation.

Selected Publications
Wang, H., Chatterjee, G., Meyer, J.J., Liu, C-J. Manjunath, N.A., Bray-Ward, P., and Lengyel, P. Characteristics of three homologous 202 genes (Ifi202a, Ifi202b and Ifi202c) from the murine interferon-activatable gene 200 cluster. Genomics, 60:281-294 (1999).

H. Wang, C.J. Liu, Y. Lu, G. Chatterjee, X-Y. Ma, R. N. Eisenman, and P. Lengyel.
The interferon- and differentiation-inducible p202a protein inhibits the transcriptional and biological activities of c-Myc by blocking its association with Max. J. Biol. Chem. 275, 27377-27385 (2000).

C.J. Liu, H. Wang, Z. Zhao, S. Yu, Y. Lu, J. Meyer, G. Chatterjee, S. Deschamps B. A. Roe and P. Lengyel. MyoD-dependent induction during myoblast differentiation of p204, a protein also inducible by interferon. Mol. Cell Biol. 20, 7024-7036 (2000).

Xin, H., D'Souza, S., Fang, L. Lengyel, P. and Choubey, D. p202, an interferon-inducible negative regulator of cell growth, is a target of the adenovirus E1A protein Oncogene, 20, 6828-6839 (2001).

Liu, C.-J., Ding, B., Wang, H. and Lengyel, P.
The MyoD-inducible p204 protein overcomes the inhibition of myoblast differentiation by Id proteins. Mol. Cell. Biol.,22, 2893-2905 (2002).

Last updated 2001