TIP49b, a Regulator of Activating Transcription Factor 2 Response to Stress and DNA Damage
Activating transcription factor-2(ATF2/CRE-BP1) is a member of the ATF-CREB family of transcription factors, which has been implicated in growth control, cell cycle progression, differentiation and transformation. Upon exposure to stress or DNA damage, JNK/p38 kinases phosphorylate T-69 and T-71, alleviating intrinsic inhibition and rendering ATF2 transcriptionally active. As a leucine zipper transcription factor, ATF2 binds an 8-bp response element(CRE/URE; 5-TGACGTCA-3; 61), as a homodimer or as a heterodimer with other members of the ATF family, as well as the Jun/Fos family of transcription factors. Although ATF-2 has been implicated in the transcriptional control of various stress-responsive genes, including c-jun, interferon-b, TGFb, and TNFa, our understanding of the biological functions of ATF2 is limited.
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(ATF2^(150-248)), 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 p38kinase, all of which induced ATF2 phosphorylation and increased TIP49b-ATF2 association. Constitutive expression of ATF2^(150-248) peptide outcompeted TIP49b interaction with ATF2 and alleviated the suppression of ATF2 transcriptional activities. Expression of ATF2^(150-248) 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.