Serum regulation of Id1 expression by a BMP pathway and BMP responsive element.
Immediate early genes (IEGs) are expressed upon re-entry of quiescent cells into the cell cycle following serum stimulation. These genes are involved in growth control and differentiation and hence their expression is tightly controlled. Many IEGs are regulated through Serum Response Elements (SREs) in their promoters, which bind Serum Response Factor (SRF). However, many other IEGs do not have SREs in their promoters and their serum regulation is poorly understood. We have identified SRF-independent IEGs in SRF-depleted fibroblasts. One of these, Id1, was examined more closely. We mapped a serum responsive element in the Id1 promoter and find that it is identical to a BMP responsive element (BRE). The Id1 BRE is necessary and sufficient for the serum regulation of Id1. Inhibition of the BMP pathway by siRNA depletion of Smad 4, treatment with the BMP antagonist noggin, or the BMP receptor inhibitor dorsomorphin blocked serum induction of Id1. Further, BMP2 is sufficient to induce Id1 expression. Given reports that SRC inhibitors can block Id1 expression, we tested the SRC inhibitor, AZD0530, and found that it inhibits the serum activation of Id1. Surprisingly, this inhibition is independent of SRC or its family members. Rather, we show that AZD0530 directly inhibits the BMP type I receptors. Serum induction of the Id1 related gene Id3 also required the BMP pathway. Given these and other findings we conclude that the Id family of IEGs is regulated by BMPs in serum through similar BREs. This represents a second pathway for serum regulation of IEGs.
Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: Tca2103@columbia.edu.
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D015153:Blotting, Western; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020218:Response Elements / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044967:Serum / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D052117:Benzodioxoles; D019485:Bone Morphogenetic Proteins; D051798:Inhibitor of Differentiation Protein 1; D011799:Quinazolines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051785:Smad Proteins; C515233:saracatinib; D008156:Luciferases; D019061:src-Family Kinases; D052004:Bone Morphogenetic Protein Receptors
AZD0530, saracatinib; BMP Response Element; Id1, inhibitor of DNA binding/differentiation 1; Immediate early gene; Serum Response Element