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Journal of Virology, March 1999, p. 2038-2044, Vol. 73, No. 3
0022-538X/99/$00.00+0

Identification of Protein Instability Determinants in the Carboxy-Terminal Region of c-Myb Removed as a Result of Retroviral Integration in Murine Monocytic Leukemias

Juraj Bies,1,2 Viktor Nazarov,1,dagger and Linda Wolff1,*

Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255,1 and Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia2

Received 23 July 1998/Accepted 20 November 1998

The c-myb oncogene has been a target of retroviral insertional mutagenesis in murine monocytic leukemias. One mechanism by which c-myb can be activated is through the integration of a retroviral provirus into the central portion of the locus, causing premature termination of c-myb transcription and translation. We had previously shown that a leukemia-specific c-Myb protein, truncated at the site of proviral integration by 248 amino acids, had approximately a fourfold-increased half-life compared to the normal c-Myb protein, due to its ability to escape rapid degradation by the ubiquitin-26S proteasome pathway. Here we provide evidence for the existence of more than one instability determinant in the carboxy-terminal region of the wild-type protein, which appear to act independently of each other. The data were derived from examination of premature termination mutants and deletion mutants of the normal protein, as well as analysis of another carboxy-terminally truncated protein expressed in leukemia. Evidence is provided that one instability determinant is located in the terminal 87 amino acids of the protein and another is located in the vicinity of the internal region that has leucine zipper homology. In leukemias, different degrees of protein stability are attained following proviral integration depending upon how many determinants are removed. Interestingly, although PEST sequences (rich in proline, glutamine, serine, and threonine), often associated with degradation, are found in c-Myb, deletion of PEST-containing regions had no effect on protein turnover. This study provides further insight into how inappropriate expression of c-Myb may contribute to leukemogenesis. In addition, it will facilitate further studies aimed at characterizing the specific role of individual regions of the normal protein in targeting to the 26S proteasome.

* Corresponding author. Mailing address: Laboratory of Cellular Oncology, National Cancer Institute, NIH, Building 37, Room 2B04, 37 Convent Dr., Bethesda, MD 20892-4255. Phone: (301) 496-6763. Fax: (301) 402-1031. E-mail: LWOLFF{at}helix.nih.gov.

dagger Present address: Institute of Molecular Biology, Slovak Academy of Sciences, Bratislava, Slovakia.

Journal of Virology, March 1999, p. 2038-2044, Vol. 73, No. 3
0022-538X/99/$00.00+0


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