Expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 and p53 tumor suppressor in dysplastic progression and adenocarcinoma in Barrett esophagus

Cancer ◽  
1999 ◽  
Vol 86 (5) ◽  
pp. 756-763 ◽  
Author(s):  
Jay S. Hanas ◽  
Megan R. Lerner ◽  
Stan A. Lightfoot ◽  
Carl Raczkowski ◽  
Donald J. Kastens ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Kinase Inhibitor ◽  
Barrett Esophagus ◽  
Cyclin Dependent Kinase ◽  
P53 Tumor Suppressor ◽  
Cyclin Dependent Kinase Inhibitor

Functional Loss of p21/Waf-1 in a Case of Benign Canine Multicentric Melanoma

1998 ◽  
Vol 35 (2) ◽  
pp. 94-101 ◽  
Author(s):  
M. G. Ritt ◽  
J. Wojcieszyn ◽  
J. F. Modiano
Keyword(s):  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
P53 Gene ◽  
Tumor Formation ◽  
Cyclin Dependent Kinase ◽  
P53 Expression ◽  
Functional Loss ◽  
Normal Tissues ◽  
Cyclin Dependent Kinase Inhibitor

Mutations of tumor suppressor genes remove mechanisms that normally arrest proliferation of transformed cells, resulting in tumor formation. The p53 gene product functions as a tumor suppressor that induces p21/Waf-1, the 21-kDa product of the waf-1/cip-1/mda-6 gene. p21/Waf-1 is a pan-cyclin-dependent kinase inhibitor that arrests cell cycle progression under a variety of circumstances. We examined tissues from a dog with multiple primary pigmented proliferative lesions (benign, multicentric melanoma consisting of three distinct dermal lesions and a matrical cyst) for p21/Waf-1 and p53 expression by immunohistochemistry and immunoblotting. p21/Waf-1 and p-53 proteins were undetectable in the tumor cells and in the cyst but were present in adjacent normal tissues. Abundant cyclin-dependent kinase 4 (Cdk4), a protein related functionally to p21/Waf-1, also was present in the cyst. A somatic mutation of the waf-1 gene or of the p53 gene may have resulted in the loss of p21/Waf-1 expression in a common precursor of pigment-producing cells from the affected dog. Furthermore, this functional loss of p21/Waf-1 may play an important role in the genesis of canine benign melanoma.

scholarly journals Roles of the Tumor Suppressor p53 and the Cyclin-dependent Kinase Inhibitor p21WAF1/CIP1 in Receptor-mediated Apoptosis of WEHI 231 B Lymphoma Cells

1998 ◽  
Vol 187 (10) ◽  
pp. 1671-1679 ◽  
Author(s):  
Min Wu ◽  
Robert E. Bellas ◽  
Jian Shen ◽  
Gail E. Sonenshein
Keyword(s):  
Tumor Suppressor ◽  
B Cell ◽  
Kinase Inhibitor ◽  
Ectopic Expression ◽  
Cyclin Dependent Kinase ◽  
Lymphoma Cells ◽  
B Lymphoma ◽  
Cyclin Dependent Kinase Inhibitor ◽  
B Lymphoma Cells ◽  
Wehi 231

Treatment of WEHI 231 immature B lymphoma cells with an antibody against their surface immunoglobulin M (anti-IgM) induces apoptosis and has been studied extensively as a model of self-induced B cell tolerance. Since the tumor suppressor protein p53 has been implicated in apoptosis in a large number of cell types and has been found to be mutated in a variety of B cell tumors, here we sought to determine whether p53 and the p53 target gene cyclin-dependent kinase inhibitor p21WAF1/CIP1 were involved in anti-IgM–induced cell death. Anti-IgM treatment of WEHI 231 cells increased expression of p53 and p21 protein levels. Ectopic expression of wild-type p53 in WEHI 231 cells induced both p21 expression and apoptosis. Ectopic expression of p21 similarly induced apoptosis. Rescue of WEHI 231 cells from apoptosis by costimulation with CD40 ligand ablated the increase in p21 expression. Lastly, a significant decrease in anti-IgM–mediated apoptosis was seen upon downregulation of endogenous p53 activity by expression of a dominant-negative p53 protein or upon microinjection of an antisense p21 expression vector or antibody. Taken together, the above data demonstrate important roles for p53 and p21 proteins in receptor-mediated apoptosis of WEHI 231 B cells.

Parathyroid Tumor Suppressor on 1p: Analysis of the p18 Cyclin-Dependent Kinase Inhibitor Gene As a Candidate

1997 ◽  
Vol 12 (9) ◽  
pp. 1330-1334 ◽  
Author(s):  
Hideki Tahara ◽  
Alison P. Smith ◽  
Randall D. Gaz ◽  
Maimoona Zariwala ◽  
Yue Xiong ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Parathyroid Tumor ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Inhibitor Gene

scholarly journals TMIGD1, a putative tumor suppressor, induces G2-M cell cycle checkpoint arrest in colon cancer cells

2020 ◽  
Author(s):  
Kyle Oliver Corcino De La Cena ◽  
Rachel Xi-Yeen Ho ◽  
Razie Amraei ◽  
Nick Woolf ◽  
Joseph Y. Tashjian ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Cell Cycle Checkpoint ◽  
Cyclin Dependent Kinase ◽  
M Cell ◽  
Poor Overall Survival ◽  
Cyclin Dependent Kinase Inhibitor

ABSTRACTColorectal cancer (CRC) is a leading non-familial cause of cancer mortality among men and women. Although various genetic and epigenetic mechanisms have been identified, the full molecular mechanisms deriving CRC tumorigenesis remains incompletely understood. In this study, we demonstrate that cell adhesion molecule transmembrane and immunoglobulin domain containing1 (TMIGD1) is highly expressed in mouse and human normal intestinal epithelial cells. We have developed TMIGD1 knockout mice and show that the loss of TMIGD1 in mice results in the development of adenomas in small intestine and colon. Additionally, the loss of TMIGD1 in mouse impaired intestinal epithelium brush border formation, junctional polarity and maturation. Mechanistically, TMIGD1 inhibits tumor cell proliferation, cell migration, arrests cell cycle at G2/M phase and induces expression of p21CIP1 (cyclin-dependent kinase inhibitor 1), and p27KIP1 (cyclin-dependent kinase inhibitor 1B) expression, key cell cycle inhibitor proteins involved in the regulation of the cell cycle. Moreover, we demonstrate that TMIGD1 is progressively downregulated in sporadic human CRC and correlates with poor overall survival. Our findings identify TMIGD1 as a novel tumor suppressor gene and provide insights into the pathogenesis of colorectal cancer and possibilities as a potential therapeutic target.

scholarly journals The Tumor Suppressor p53 and Histone Deacetylase 1 Are Antagonistic Regulators of the Cyclin-Dependent Kinase Inhibitor p21/WAF1/CIP1 Gene

2003 ◽  
Vol 23 (8) ◽  
pp. 2669-2679 ◽  
Author(s):  
Gerda Lagger ◽  
Angelika Doetzlhofer ◽  
Bernd Schuettengruber ◽  
Eva Haidweger ◽  
Elisabeth Simboeck ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Histone Deacetylase ◽  
Kinase Inhibitor ◽  
Genotoxic Stress ◽  
Cyclin Dependent Kinase ◽  
Tumor Suppressor P53 ◽  
Histone Deacetylase 1 ◽  
Cyclin Dependent Kinase Inhibitor ◽  
C Terminus ◽  
P21 Promoter

ABSTRACT The cyclin-dependent kinase inhibitor p21/WAF1/CIP1 is an important regulator of cell cycle progression, senescence, and differentiation. Genotoxic stress leads to activation of the tumor suppressor p53 and subsequently to induction of p21 expression. Here we show that the tumor suppressor p53 cooperates with the transcription factor Sp1 in the activation of the p21 promoter, whereas histone deacetylase 1 (HDAC1) counteracts p53-induced transcription from the p21 gene. The p53 protein binds directly to the C terminus of Sp1, a domain which was previously shown to be required for the interaction with HDAC1. Induction of p53 in response to DNA-damaging agents resulted in the formation of p53-Sp1 complexes and simultaneous dissociation of HDAC1 from the C terminus of Sp1. Chromatin immunoprecipitation experiments demonstrated the association of HDAC1 with the p21 gene in proliferating cells. Genotoxic stress led to recruitment of p53, reduced binding of HDAC1, and hyperacetylation of core histones at the p21 promoter. Our findings show that the deacetylase HDAC1 acts as an antagonist of the tumor suppressor p53 in the regulation of the cyclin-dependent kinase inhibitor p21 and provide a basis for understanding the function of histone deacetylase inhibitors as antitumor drugs.

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