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Molecular and Cellular Biology, January 2004, p. 487-501, Vol. 24, No. 2
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.2.487-501.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

{Delta}Np73ß Is Active in Transactivation and Growth Suppression

Gang Liu, Susan Nozell, Hui Xiao, and Xinbin Chen*

Department of Cell Biology, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0005

Received 29 May 2003/ Returned for modification 30 July 2003/ Accepted 23 October 2003

p73, a p53 family protein, shares significant sequence homolog and functional similarity with p53. However, unlike p53, p73 has at least seven alternatively spliced isoforms with different carboxyl termini (p73{alpha}-{eta}). Moreover, the p73 gene can be transcribed from a cryptic promoter located in intron 3, producing seven more proteins ({Delta}Np73{alpha}-{eta}). {Delta}Np73, which does not contain the N-terminal activation domain in p73, has been thought to be transcriptionally inactive and dominant negative over p53 or p73. To systemically analyze the activity of the {Delta}N variant, we generated stable cell lines, which inducibly express {Delta}Np73{alpha}, {Delta}Np73ß, and various {Delta}Np73ß mutants by using the tetracycline-inducible expression system. Surprisingly, we found that {Delta}Np73ß is indeed active in inducing cell cycle arrest and apoptosis. Importantly, we found that, when {Delta}Np73ß is expressed at a physiologically relevant level, it is capable of suppressing cell growth. We then demonstrated that these {Delta}Np73ß activities are not cell type specific. We showed that the 13 unique residues at the N terminus are required for {Delta}Np73ß to suppress cell growth. We also found that, among the 13 residues, residues 6 to 10 are critical to {Delta}Np73ß function. Furthermore, we found that {Delta}Np73ß is capable of inducing some p53 target genes, albeit to a lesser extent than does p73ß. Finally, we found that the 13 unique residues, together with the N-terminal PXXP motifs, constitute a novel activation domain. Like {Delta}Np73ß, {Delta}Np73{gamma} is active in transactivation. However, unlike {Delta}Np73ß, {Delta}Np73{alpha} is inactive in suppressing cell growth. Our data, together with others' previous findings, suggest that {Delta}Np73ß may have distinct functions under certain cellular circumstances.

* Corresponding author. Mailing address: MCLM 660, Department of Cell Biology, The University of Alabama at Birmingham, 1530 3rd Ave. S., Birmingham, AL 35294-0005. Phone: (205) 975-1798. Fax: (205) 934-0950. E-mail: xchen{at}uab.edu.

Molecular and Cellular Biology, January 2004, p. 487-501, Vol. 24, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.2.487-501.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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