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Cell Division Cycle 7 is Essential for the Initiation of Transforming Growth Factor‐β‐induced Smooth Muscle Differentiation

The objective of this study was to determine if cell division cycle 7 (Cdc7) plays a role in smooth muscle cell (SMC) differentiation. Cdc7 stimulates cell proliferation by facilitating the initiation of DNA replication. We found that Cdc7 is also important for the initiation of SMC differentiation. TGF‐β induced an increased Cdc7 expression and phosphorylation in the initial phase of SMC differentiation. Cdc7 specific inhibitor or shRNA suppressed TGF‐β‐induced expression of SMC early marker genes α‐SMA, SM22α and calponin. Cdc7 overexpression, on the other hand, enhanced the marker expression in a dose‐dependent manner. Cdc7 function in SMC markers was independent of DBF4, the catalytic subunit of Cdc7 critical for cell proliferation, suggesting that Cdc7 mediates SMC differentiation through a mechanism distinct from that of cell proliferation. Cdc7 appeared to be involved in activating SMC gene transcription. ShRNA knockdown of Cdc7 inhibited TGF‐β‐induced SMC marker promoter activity, while overexpression of Cdc7 activated the promoter activities. Importantly, CArG mutation diminished Cdc7‐induced activation of α‐SMA and SM22α promoters, suggesting that Cdc7‐induced SMC differentiation is SRF‐dependent. Taken together, our data demonstrate a novel role for Cdc7 in regulating the early phase of TGF‐β‐induced SMC differentiation. (Funding source: NIH R01HL093429)