Human non-Hodgkin's lymphomas overexpress a wild-type form of p53 which is a functional transcriptional activator of the cyclin-dependent kinase inhibitor p21.
A large fraction of non-Hodgkin's lymphomas (NHLs) accumulate a wild-type form of the p53 tumor suppressor protein at the nuclear level. In normal cells, p53 induction is associated with a temporary cell growth arrest at the G1-S boundary of the cell cycle. This activity of p53 as a G1 checkpoint molecule is strictly dependent on its ability to induce the transcription of the inhibitor of the cyclin dependent kinase, p21. To verify the functionality of the wild-type p53 protein accumulated in NHL cells, 70 cases were comparatively analyzed for p53 and p21 expression and status of the respective genes. Overexpression of the wt p53 protein was associated with the accumulation of p21, indicating that p53 is functional with respect to p21 induction in these tumors. The coaccumulation of p53 with Ki-67 antigen indicates that wt p53-positive cells and p21-positive cells, as well, are actively proliferative elements, supporting the notion that p53-induced, p21-mediated growth arrest is somehow overridden in NHL cells. No p21 mutation or particular allele variant was shown to correlate with p21 protein accumulation, thus excluding a role for p21 structural abnormalities. Taken together, our data suggest the existence in NHL of a peculiar mechanism of functional inactivation of the p53 G1 checkpoint pathway occurring downstream of the CDK inhibitor p21.
Maestro
R
R
Department of Experimental Oncology 1, Centro di Riferimento Oncologico, Aviano, Italy.
Gloghini
A
A
Doglioni
C
C
Piccinin
S
S
Vukosavljevic
T
T
Gasparotto
D
D
Carbone
A
A
Boiocchi
M
M
D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis / Q000235:genetics; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53