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Molecular and Cellular Biology, December 2001, p. 8398-8413, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8398-8413.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

TIP49b, a Regulator of Activating Transcription Factor 2 Response to Stress and DNA Damage

Ssang-Goo Cho,1 Anindita Bhoumik,1 Limor Broday,1 Vladimir Ivanov,1 Barry Rosenstein,2 and Ze'ev Ronai1,*

The Ruttenberg Cancer Center1 and Department of Radiology,2 Mount Sinai School of Medicine, New York, New York 10029

Received 11 July 2001/Returned for modification 5 September 2001/Accepted 19 September 2001

Activating transcription factor 2 (ATF2/CRE-BP1) is implicated in transcriptional control of stress-responsive genes. A yeast two-hybrid screen identified TBP-interacting protein 49b (TIP49b), a component of the INO80 chromatin-remodeling complex, as a novel ATF2-interacting protein. TIP49b's association with ATF2 is phosphorylation dependent and requires amino acids 150 to 248 of ATF2 (ATF2150-248), which are implicated in intramolecular inhibition of ATF2 transcriptional activities. Forced expression of TIP49b efficiently attenuated ATF2 transcriptional activities under normal growth conditions as well as after UV treatment, ionizing irradiation, or activation of p38 kinase, all of which induced ATF2 phosphorylation and increased TIP49b-ATF2 association. Constitutive expression of ATF2150-248 peptide outcompeted TIP49b interaction with ATF2 and alleviated the suppression of ATF2 transcriptional activities. Expression of ATF2150-248 in fibroblasts or melanoma but not in ATF2-null cells caused a profound G2M arrest and increased degree of apoptosis following irradiation. The interaction between ATF2 and TIP49b constitutes a novel mechanism that serves to limit ATF2 transcriptional activities and highlights the central role of ATF2 in the control of the cell cycle and apoptosis in response to stress and DNA damage.

* Corresponding author. Mailing address: Ruttenberg Cancer Center, Mount Sinai School of Medicine, 1 Gustave Levy Place, Box 1130, New York, NY 10029. Phone: (212) 659-5571. Fax: (212) 849-2425. E-mail: zeev.ronai{at}mssm.edu.

Molecular and Cellular Biology, December 2001, p. 8398-8413, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8398-8413.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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