Inhibition of Cell Growth by Transforming Growth Factor Beta 1 is Associated with P53-independent Induction of P21 in Gastric Carcinoma Cells

Overview

Journal Jpn J Cancer Res

Specialty Oncology

Date 1996 Apr 1

PMID 8641969

Citations 10

Authors

M Akagi

W Yasui

Y Akama

H Yokozaki

H Tahara

K Haruma

G Kajiyama

E Tahara

Affiliations

Soon will be listed here.

Abstract

Cell cycle regulators such as cyclins, cyclin-dependent kinases (cdks) and their inhibitors control the growth of cells. SDI1/CIP1/WAF1/p21 is a potent inhibitor of G1 cdks, whose expression is induced by wild-type p53. To elucidate the mechanism of growth inhibition by transforming growth factor beta 1 (TGFbeta 1), we examined the effect of TGFbeta 1 on the expression of p21, G1 cyclins and cdks by human gastric cancer cell lines. TGFbeta 1 induced p21 expression and subsequently suppressed cdk2 kinase activity, followed by a reduction in phosphorylation of the product of the retinoblastoma tumor suppressor gene in TMK-1 cells, which are responsive to TGFbeta 1. Coimmunoprecipitation analysis demonstrated that TGFbeta 1 increased the level of p21 protein present in complexes with cdk2. In contrast, TGFbeta 1 did not induce p21 in TGFbeta 1-resistant MKN-28 cells. TGFbeta 1 did not affect the levels of p53 mRNA and protein in TMK-1 and MKN-28 cells, which contain mutated p53 genes. These mutated p53 complementary DNAs, when overexpressed, failed to activate transcription from the p21 promoter. Furthermore, TGFbeta 1 caused a reduction in the steady-state level of cyclin A protein concomitantly with inhibition of cdk2 kinase activity in TMK-1 cells. These results suggest that the growth inhibition of tumor cells by TGFbeta 1 is associated with p53-independent induction of p21, subsequent suppression of cdk activity and a decrease in cyclin A protein in TMK-1 cells.

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References

Toyoshima H, Hunter T . p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 1994; 78(1):67-74. DOI: 10.1016/0092-8674(94)90573-8. View

Greenblatt M, BENNETT W, Hollstein M, Harris C . Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994; 54(18):4855-78. View

Yoshida K, Kyo E, Tsujino T, Sano T, Niimoto M, Tahara E . Expression of epidermal growth factor, transforming growth factor-alpha and their receptor genes in human gastric carcinomas; implication for autocrine growth. Jpn J Cancer Res. 1990; 81(1):43-51. PMC: 5917953. DOI: 10.1111/j.1349-7006.1990.tb02505.x. View

Polyak K, Kato J, Solomon M, Sherr C, Massague J, Roberts J . p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 1994; 8(1):9-22. DOI: 10.1101/gad.8.1.9. View

Koff A, Ohtsuki M, Polyak K, Roberts J, Massague J . Negative regulation of G1 in mammalian cells: inhibition of cyclin E-dependent kinase by TGF-beta. Science. 1993; 260(5107):536-9. DOI: 10.1126/science.8475385. View

Geng Y, Weinberg R . Transforming growth factor beta effects on expression of G1 cyclins and cyclin-dependent protein kinases. Proc Natl Acad Sci U S A. 1993; 90(21):10315-9. PMC: 47765. DOI: 10.1073/pnas.90.21.10315. View

Dulic V, Kaufmann W, Wilson S, Tlsty T, Lees E, Harper J . p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell. 1994; 76(6):1013-23. DOI: 10.1016/0092-8674(94)90379-4. View

Alexandrow M, Moses H . Transforming growth factor beta and cell cycle regulation. Cancer Res. 1995; 55(7):1452-7. View

Ito M, Yasui W, Kyo E, Yokozaki H, Nakayama H, Ito H . Growth inhibition of transforming growth factor beta on human gastric carcinoma cells: receptor and postreceptor signaling. Cancer Res. 1992; 52(2):295-300. View

10.

Ito M, Yasui W, Nakayama H, Yokozaki H, Ito H, Tahara E . Reduced levels of transforming growth factor-beta type I receptor in human gastric carcinomas. Jpn J Cancer Res. 1992; 83(1):86-92. PMC: 5918645. DOI: 10.1111/j.1349-7006.1992.tb02356.x. View

11.

Weinberg R . The retinoblastoma protein and cell cycle control. Cell. 1995; 81(3):323-30. DOI: 10.1016/0092-8674(95)90385-2. View

12.

El-Deiry W, Tokino T, Velculescu V, Levy D, Parsons R, Trent J . WAF1, a potential mediator of p53 tumor suppression. Cell. 1993; 75(4):817-25. DOI: 10.1016/0092-8674(93)90500-p. View

13.

Barlat I, Henglein B, Plet A, Lamb N, Fernandez A, McKenzie F . TGF-beta 1 and cAMP attenuate cyclin A gene transcription via a cAMP responsive element through independent pathways. Oncogene. 1995; 11(7):1309-18. View

14.

Ochiai A, Yasui W, Tahara E . Growth-promoting effect of gastrin on human gastric carcinoma cell line TMK-1. Jpn J Cancer Res. 1985; 76(11):1064-71. View

15.

Myeroff L, Parsons R, Kim S, Hedrick L, Cho K, Orth K . A transforming growth factor beta receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res. 1995; 55(23):5545-7. View

16.

Ko T, Sheng H, Reisman D, Thompson E, Beauchamp R . Transforming growth factor-beta 1 inhibits cyclin D1 expression in intestinal epithelial cells. Oncogene. 1995; 10(1):177-84. View

17.

Hannon G, Beach D . p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 1994; 371(6494):257-61. DOI: 10.1038/371257a0. View

18.

Yoshida K, Yokozaki H, Niimoto M, Ito H, Ito M, Tahara E . Expression of TGF-beta and procollagen type I and type III in human gastric carcinomas. Int J Cancer. 1989; 44(3):394-8. DOI: 10.1002/ijc.2910440303. View

19.

Barlat I, Fesquet D, Brechot C, Henglein B, Dupuy dAngeac A, Vie A . Loss of the G1-S control of cyclin A expression during tumoral progression of Chinese hamster lung fibroblasts. Cell Growth Differ. 1993; 4(2):105-13. View

20.

Michieli P, Chedid M, Lin D, PIERCE J, Mercer W, Givol D . Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res. 1994; 54(13):3391-5. View