Cell Division Cycle 7 Is a Novel Regulator of Transforming Growth Factor-β-induced Smooth Muscle Cell Differentiation

Abstract

Background: Cell differentiation and proliferation are regulated simultaneously during early development, but the underlying mechanisms remain largely unknown. Results: Cell division cycle 7 (Cdc7) regulates TGF-␤-induced smooth muscle cell differentiation. Conclusion: Cdc7 is likely a common factor regulating both cell proliferation and differentiation. Significance: Our data provide a novel mechanism governing the synchronized regulation of cell proliferation and differentiation.

Cell Division Cycle 7 Mediates Transforming Growth Factor-β-induced Smooth Muscle Maturation through Activation of Myocardin Gene Transcription

“…The present study together with our recently published results (20,37) provide a model for Cdc7 function in the initial and late phase of TGF-␤-induced SM differentiation, i.e. upon TGF-␤ stimulation, Smad3 is activated and translocated to nucleus where it binds to Cdc7 and Nkx2.5.…”

“…TGF-␤ also regulates cell proliferation in different physiological contexts (8,(17)(18)(19). Our previous studies have shown that cell division cycle 7 (Cdc7), a cell cycle regulator facilitating initiation of DNA replication, regulates the initiation program of TGF-␤-induced SM differentiation via interaction with Smad3 while stimulating cell proliferation (20). It is unknown, however, whether Cdc7 plays a role in SM maturation.…”

“…Myocd primers were 5Ј-ACC CAT GGA CTC TGC CTA TG-3Ј (forward) and 5Ј-AGG GGT ATT GCT CAG TGG TG-3Ј (reverse). Nkx2.5 binding site and Cdc7 primers were reported previously (20).…”

“…Maturation-Our previous study has shown that Cdc7 plays a role in initiating TGF-␤-induced SM differentiation (20). To determine whether Cdc7 is important for SM maturation, we examined the expression of Cdc7 along with the mature SM marker SMMHC in cells treated with TGF-␤ for up to 48 h, a time past the initial stage of SM differentiation.…”

Characterization of a Drosophila Ortholog of the Cdc7 Kinase

“…This explanation would be consistent with the inability of Cdc7 to rescue the mitotic growth defect of cdc7-90 yeast in the absence of Chiffon. A recent study has shown that Dbf4 knockdown has no effect on Cdc7-dependent induction of smooth muscle cell differentiation in murine cell lines, which is instead dependent on interactions between Cdc7 and the SMAD3 transcriptional modulator (92). Thus, there is a precedent for the ability of Cdc7 to function in specific developmental processes independently of Dbf4, potentially through interactions with other unrelated factors.…”