Transforming growth factor beta effects on expression of G1 cyclins and cyclin-dependent protein kinases.

Abstract

Transforming growth factor (31 (TGF-f81) is a potent growth-inhibitory polypeptide. The mechanism of TGF-13, inhibition has been related to its ability to prevent the hyperphosphorylation of retinoblastoma protein (pRb). Several lines of evidence have suggested that cell cycle-regulated protein kinases are responsible for the hyperphosphorylation of pRb. We demonstrate here that TGF-fi1 has profound effects on the expression of genes encoding certain Gl cyclins and their associated kinases, which provides one explanation of TGF-p1 effects on pRb hyperphosphorylation. These results also suggest that the growth-inhibitory effects of TGF-813 in many cells are attributable to its effects on the cell cycle apparatus involved in programming Gl transit. Several cellular genes that are important in the control of cell proliferation have been shown to be affected by TGF-/31 treatment-e.g., the transcription of the c-myc gene is inhibited by TGF-31 (5). The negative growth effects of TGF-/31 have been linked to a tumor suppressor gene product, the retinoblastoma protein, pRb. Specifically, it has been shown that upon TGF-,31 treatment, the hyperphosphorylation of pRb is prevented, pRb remains hypophosphorylated, and cells become arrested in late Gl (3). Since the hyperphosphorylation of pRb, which normally occurs in late Gl, is thought to represent a molecular switch that converts pRb from an active growth-suppressing form into an inactive form (6-9), it has been hypothesized that TGF-,31 exerts its inhibitory effects on the cell cycle progression by preventing this hyperphosphorylation.Because hyperphosphorylation of pRb appears to be the key regulator of its function, the identity of the responsible kinases has attracted much interest. Tryptic mapping of the sites of phosphorylation on pRb in vivo suggested that pRb is phosphorylated by a subset of cdc2-related kinases, termed cyclin-dependent protein kinases (cdks) (10,11). Recently a number of known or putative cdks have been described (12, 13). The activity and substrate specificity of cdks are thought to be regulated in turn by association with their regulatory subunits, the cyclins. Five classes of mammalian cyclins haveThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. been enumerated to date: A, B (including Bi and B2), C, D (including Dl, D2, and D3), and E (14-17).These various cyclins have been assigned roles in specific phases of the cell cycle. Thus, cyclin B in association with cdc2 has been shown to promote G2/M transition (18). The expression of cyclin A occurs at the onset of S phase, and this cyclin associates with both cdc2 and cdk2 (12,19,20). Cyclins C, D, and E are defined as Gl cyclins, as their expression occurs mainly in Gl. The expression of cyclin E occurs with sudden onset in mid/late Gl in parallel with the appearance of cyclin E'cdk2 complexes having strong kinase activity (15,...

Estrogen-Dependent Cyclin E-cdk2 Activation through p21 Redistribution

“…However, these studies did not evaluate the effect of tamoxifen on the cell cycle machinery. The period of responsiveness to tamoxifen in G 1 is reminiscent of the effects of transforming growth factor ␤ (TGF-␤) on cell cycle advance, which are known to involve primarily a blockage of pRb phosphorylation (14,25). Thus, after cells have phosphorylated their complement of pRb in late G 1 , they become nonresponsive to the growth-inhibitory effects of TGF-␤.…”

SRF is a nuclear repressor of Smad3-mediated TGF-β signaling

“…Recent studies demonstrated that SRF was overabundant and highly active in epithelial tumor cells that had undergone mesenchymal transition (Geng and Weinberg, 1993). The elevated SRF DNA-binding activity correlated with the increased expression of SRF itself, and with actin and vinculin, which are both SRFdependent genes.…”

“…This effect is mediated by several events that are activated downstream of the TGF-b receptor. This includes the transcriptional repression of the proto-oncogene c-myc (Alexandrow et al, 1995), downmodulation of the expression and activities of G1 and G2 CDK and cyclins (Ewen et al, 1993;Geng and Weinberg, 1993;Iavarone and Massague, 1997), and activation of the genes encoding p15 INK4b (Hannon and Beach, 1994), p21 Cip1 (Datto et al, 1995;Claassen and Hann, 2000) and p27 Kip1 (Polyak et al, 1994;Depoortere et al, 2000) that encode CDK inhibitors. Previously, it was demonstrated that Smads functionally cooperate with Sp1 to activate the human p21 Cip1 and p15 INK4b promoters.…”

c-ETS1 Facilitates G1/S-phase Transition by Up-regulating Cyclin E and CDK2 Genes and Cooperates with Hepatitis B Virus X Protein for Their Deregulation

“…In contrast, CDK2 regulation has been studied mainly at post translational level (13), and only a few reports have discussed the oscillation of CDK2 levels before S-phase entry (14,15). This suggests that the regulation of CDK2 at the transcriptional level could be as important as its post-translational control.…”