Interaction of the regulatory subunit of the cAMP-dependent protein kinase with PATZ1 (ZNF278).
The effects of cAMP in cell are predominantly mediated by the cAMP-dependent protein kinase (PKA), which is composed of two genetically distinct subunits, catalytic (C) and regulatory (R), forming a tetrameric holoenzyme R(2)C(2). The only known function for the R subunit is that of inhibiting the activity of the C subunit kinase. It has been shown that overexpression of RIalpha, but not the C subunit kinase, is associated with neoplastic transformation. In addition, it has also been demonstrated that mutation in the RIalpha, but not the C subunit is associated with increased resistance to the DNA-damaging anticancer drug cisplatin, thus suggesting that the RIalpha subunit of PKA may have functions independent of the kinase. We show here that the RIalpha subunit interacts with a BTB/POZ domain zinc-finger transcription factor, PATZ1 (ZNF278), and co-expression with RIalpha results in its sequestration in the cytoplasm. The cytoplasmic/nuclear translocation is inducible by cAMP. C-terminus deletion abolishes PATZ1 interaction with RIalpha and results in its localization in the nucleus. PATZ1 transactivates the cMyc promoter and the presence of cAMP and co-expression with RIalpha modulates its transactivation. Moreover, PATZ1 is aberrantly expressed in cancer. Taken together, our results showed a potentially novel mechanism of cAMP signaling mediated through the interaction of RIalpha with PATZ1 that is independent of the kinase activity of PKA, and the aberrant expression of PATZ1 in cancer point to its role in cell growth regulation.
Yang
Weng-Lang
WL
Long Island Jewish Medical Center, North Shore University Hospital, Manhasset, NY 11030, USA.
Ravatn
Roald
R
Kudoh
Kazuya
K
Alabanza
Leah
L
Chin
Khew-Voon
KV
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques; D016335:Zinc Fingers
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; C412784:PATZ1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D000242:Cyclic AMP