p53 functions as a cell cycle control protein in osteosarcomas.

Mutations in the p53 gene have been associated with a wide range of human tumors, including osteosarcomas. Although it has been shown that wild-type p53 can block the ability of E1a and ras to cotransform primary rodent cells, it is poorly understood why inactivation of the p53 gene is important for tumor formation. We show that overexpression of the gene encoding wild-type p53 blocks the growth of osteosarcoma cells. The growth arrest was determined to be due to an inability of the transfected cells to progress into S phase. This suggests that the role of the p53 gene as an antioncogene may be in controlling the cell cycle in a fashion analogous to the check-point control genes in Saccharomyces cerevisiae.

Download Full-text

P53-dependent suppression of the human calcyclin gene (S100A6): the role of Sp1 and of NFkappaB.

Acta Biochimica Polonica ◽

10.18388/abp.2008_3062 ◽

2008 ◽

Vol 55 (3) ◽

pp. 559-570 ◽

Cited By ~ 6

Author(s):

Weronika Króliczak ◽

Maciej Pietrzak ◽

Monika Puzianowska-Kuznicka

Keyword(s):

Cell Cycle ◽

Cell Cycle Control ◽

Inhibitory Effect ◽

Dependent Manner ◽

Wild Type ◽

Lower Efficiency ◽

Wild Type P53 ◽

Cell Cycle Deregulation ◽

Cancer Tissues

Calcyclin (S100A6) is believed to participate in cell cycle control. It was, however, unclear if its expression depends on p53, a key regulator of apoptosis and cell cycle. We therefore performed transcription regulation assays in HeLa cells and found that wild type p53 suppressed the S100A6 promoter up to 12-fold in a dose-dependent manner. In contrast, the well-characterized V143A, R175H, R249S, and L344A p53 mutants cloned from human cancers suppressed this promoter with a 6 to 9-fold lower efficiency. All the sites mediating the p53-dependent suppression were contained in the -167 to +134 fragment of the S100A6 promoter. Separate overexpression of either Sp1 or of NFkappaB only partially counteracted the p53 inhibitory effect on the S100A6 promoter, while simultaneous overexpression of both these transactivators resulted in a complete abolishment of the p53 inhibitory effect on this promoter. Sp1 and NFkappaB binding to the probes resembling their putative binding sites present in the S100A6 promoter was decreased in the presence of wild type p53. We propose that the suppression of S100A6 is yet another mechanism by which p53 inhibits proliferation. Insufficient suppression of this gene by p53 mutants could well be responsible for calcyclin overexpression and cell cycle deregulation observed in cancer tissues.

Download Full-text

Wild-type p53 gene expression induces granulocytic differentiation of HL-60 cells

Blood ◽

10.1182/blood.v83.8.2230.2230 ◽

1994 ◽

Vol 83 (8) ◽

pp. 2230-2237 ◽

Cited By ~ 35

Author(s):

S Soddu ◽

G Blandino ◽

G Citro ◽

R Scardigli ◽

G Piaggio ◽

...

Keyword(s):

Cell Cycle ◽

Cellular Response ◽

P53 Protein ◽

Cell Cycle Control ◽

P53 Gene ◽

Malignant Cell ◽

Temperature Sensitive ◽

Wild Type ◽

Granulocytic Differentiation ◽

Wild Type P53

Abstract Overexpression of wild-type p53 gene in malignant cell lines has been shown to inhibit cell proliferation in a number of cases. However, endogenous p53 protein seems to play little role in normal cell-cycle control as suggested by the normal development of p53 null mice, and by the low p53 protein levels expressed in most cell types. Recently, increased expression of endogenous p53 protein has been observed during the cellular response to DNA damage, as well as during differentiation of human hematopoietic cells. To study the role of the p53 gene in hematopoietic differentiation, we introduced the wild-type p53 gene or the temperature-sensitive p53(Val135) mutant into p53-deficient HL-60 promyelocytic leukemia cells. Morphological analysis, flow-cytometric determination of granulocytic or monocytic surface markers, and ability to reduce nitroblue tetrazolium (NBT) demonstrated that expression of exogenous wild-type p53 gene in HL-60 cells induces differentiation through the granulocytic pathway. Proliferation and cell-cycle analysis performed early after expression of wild-type p53 showed that induction of differentiation is not coupled with growth arrest, which suggests that p53 is involved in differentiation independently of its activity on the cell cycle.

Download Full-text

Wild-type p53 gene expression induces granulocytic differentiation of HL-60 cells

Blood ◽

10.1182/blood.v83.8.2230.bloodjournal8382230 ◽

1994 ◽

Vol 83 (8) ◽

pp. 2230-2237 ◽

Cited By ~ 2

Author(s):

S Soddu ◽

G Blandino ◽

G Citro ◽

R Scardigli ◽

G Piaggio ◽

...

Keyword(s):

Cell Cycle ◽

Cellular Response ◽

P53 Protein ◽

Cell Cycle Control ◽

P53 Gene ◽

Malignant Cell ◽

Temperature Sensitive ◽

Wild Type ◽

Granulocytic Differentiation ◽

Wild Type P53

Overexpression of wild-type p53 gene in malignant cell lines has been shown to inhibit cell proliferation in a number of cases. However, endogenous p53 protein seems to play little role in normal cell-cycle control as suggested by the normal development of p53 null mice, and by the low p53 protein levels expressed in most cell types. Recently, increased expression of endogenous p53 protein has been observed during the cellular response to DNA damage, as well as during differentiation of human hematopoietic cells. To study the role of the p53 gene in hematopoietic differentiation, we introduced the wild-type p53 gene or the temperature-sensitive p53(Val135) mutant into p53-deficient HL-60 promyelocytic leukemia cells. Morphological analysis, flow-cytometric determination of granulocytic or monocytic surface markers, and ability to reduce nitroblue tetrazolium (NBT) demonstrated that expression of exogenous wild-type p53 gene in HL-60 cells induces differentiation through the granulocytic pathway. Proliferation and cell-cycle analysis performed early after expression of wild-type p53 showed that induction of differentiation is not coupled with growth arrest, which suggests that p53 is involved in differentiation independently of its activity on the cell cycle.

Download Full-text

Role of P53 Mutations in the Radiosensitivity Status of Tumor Cells

Tumori Journal ◽

10.1177/030089169808400501 ◽

1998 ◽

Vol 84 (5) ◽

pp. 517-520 ◽

Cited By ~ 15

Author(s):

Vincenzo Chiarugi ◽

Lucia Magnelli ◽

Marina Cinelli

Keyword(s):

Dna Damage ◽

Cellular Response ◽

P53 Protein ◽

Cell Cycle Control ◽

P53 Mutations ◽

Wild Type ◽

Bladder Tumors ◽

Variable Effect ◽

Wild Type P53

Wild-type p53 is involved in cellular response to DNA damage including cell cycle control, DNA repair and activation of apoptosis. Accumulation of p53 protein following DNA damage may initiate the apoptotic process, resulting in cell death. DNA damage induced by radiation is an example of apoptotic stimulus involving p53. Regulation of apoptosis by p53 can occur through transcriptional regulation of pro-apoptotic (e.g. bax) and anti-apoptotic (e.g. bel-2) factors. Although wild-type p53 usually sensitizes cells to radiation therapy, p53 mutations have a variable effect on radiation response. For example p53 mutations in bone or breast tumors have been found to be associated with resistance to chemotherapeutic drugs or ionizing radiation. Mutated p53 has has been reported to increase sensitivity to radiation and drugs in colorectal and bladder tumors. The present brief commentary tries to find an explanation at molecular level of these conflicting results.

Download Full-text

Wild-type p53 is a cell cycle checkpoint determinant following irradiation.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.89.16.7491 ◽

1992 ◽

Vol 89 (16) ◽

pp. 7491-7495 ◽

Cited By ~ 1005

Author(s):

S. J. Kuerbitz ◽

B. S. Plunkett ◽

W. V. Walsh ◽

M. B. Kastan

Keyword(s):

Cell Cycle ◽

Cell Cycle Checkpoint ◽

Wild Type ◽

Cycle Checkpoint ◽

A Cell ◽

Wild Type P53

Download Full-text

Wild-type p53 gene transfer resulted in cell cycle arrest, but not apoptosis of newly established human malignant fibrous histiocytoma cell line.

International Journal of Oncology ◽

10.3892/ijo.15.5.935 ◽

1999 ◽

Author(s):

K Endo ◽

T Sakatani ◽

M Watanabe ◽

H Yoshida ◽

E Nanba ◽

...

Keyword(s):

Cell Cycle ◽

Gene Transfer ◽

Cell Cycle Arrest ◽

Cell Line ◽

Malignant Fibrous Histiocytoma ◽

Fibrous Histiocytoma ◽

P53 Gene ◽

Wild Type ◽

Cycle Arrest ◽

Wild Type P53

Download Full-text

Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles

Cell ◽

10.1016/0092-8674(92)90244-7 ◽

1992 ◽

Vol 70 (6) ◽

pp. 937-948 ◽

Cited By ~ 676

Author(s):

Yuxin Yin ◽

Michael A. Tainsky ◽

Farideh Z. Bischoff ◽

Louise C. Strong ◽

Geoffrey M. Wahl

Keyword(s):

Cell Cycle ◽

Gene Amplification ◽

Cell Cycle Control ◽

Mutant P53 ◽

Wild Type ◽

Wild Type P53 ◽

In Cells

Download Full-text

An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression

Cell Death and Disease ◽

10.1038/s41419-021-03934-y ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Thao Thi Thanh Nguyen ◽

Masato Shingyoji ◽

Michiko Hanazono ◽

Boya Zhong ◽

Takao Morinaga ◽

...

Keyword(s):

Wild Type ◽

Inhibitory Effects ◽

Cytotoxic Effects ◽

P53 Expression ◽

Nuclear Factor I ◽

Infected Cells ◽

Wild Type P53 ◽

Mdm2 Inhibitor ◽

P16 Expression

AbstractA majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.

Download Full-text