Role of p53 in normal suppression of proliferation

The absence of major defects in TP53-deficient mice (aside from cancer susceptibility) has contributed to the misconception that the p53 protein may not exert any essential role in ''normal life'', its activity being restricted to protection from tumorigenic DNA damage. This, however, is an oversimplification. If studies in TP53-deficient mice clearly show that absence of p53 is not lethal, the presence of p53 may represent a very serious problem that cells need to overcome for normal development, cell growth and differentiation (Montes et al., 1995). Spontaneous DNA damage occurs at rates of several thousand events per cell and per day, and p53 activation must be kept under tight control when the damage remains within the boundaries that can be safely handled by DNA repair systems. On the other hand, growth signaling itself activates p53 as a consequence of transcriptional activation of p14Arf by factors of the E2F family, which are at the receiving end of many signaling cascades stimulated by growth factors. Since p14Arf binds Mdm2 and releases it from interacting with p53, many pro-liferative signals have the potential to activate p53. This mechanism works as a safeguard against untimely and unprogrammed growth stimuli (Lomazzi et al., 2002). Nevertheless, cells must keep it under control in order to allow normal cells to proceed into mitosis when requested.

Several mechanisms are likely to participate in the neutralization of p53 function when its activity is detrimental to normal cell life. For example, downregulation of p53 expression by c-Jun contributes to lower the levels of p53 protein at the G1/S transition, coinciding with the point where p14Arf is also expressed as a result of activation by E2F (Lomazzi etal., 2002; Schreiber etal., 1999). On the other hand, the DeltaNp53 isoform appears to accumulate during G1 and to reach a level that is higher than that of full-length p53 at the G1/S transition. Since DeltaNp53 lacks the transcription activation domain, it can work as a dominant negative inhibitor of p53 to allow cells to proceed into the cell-cycle (Courtois et al., 2002). Overall, these mechanisms act in a co-ordinated manner as ''buffers'' against untimely p53 activation. Recently, two transcription regulators, YY1 and ELL, have been shown to negatively regulate p53 by preventing it from recruiting the transcription

Table 16.1. A selection of effectors of p53 functions

Factor

Activity

Mode of regulation

Function

Apo-1/Fas/CD95

Death signaling receptor

Transcriptional activation

Apoptosis

Bax-1

Dominant-negative inhibitor of bcl2

Transcriptional activation

Apoptosis

Bcl-2

Repressor of apoptosis through

Transcriptional repression

Apoptosis

control of mitochondrial

permeability

IGF-BP3

Inhibitor of IGF-I

Transcriptional activation

Apoptosis

Killer/DR5

Death signaling receptor

Transcriptional activation

Apoptosis

p85

Regulatory subunit of PI3 kinase

Transcriptional activation

Apoptosis

Pig-12

Glutathione transferase homologue

Transcriptional activation

Apoptosis

Pig-3

Quinone oxidase homologue

Transcriptional activation

Apoptosis

Pig-6

Proline oxidase homologue

Transcriptional activation

Apoptosis

IGF-I

Growth factor

Transcriptional repression

Apoptosis

IL-6

Survival factor

Transcriptional repression

Apoptosis

Thrombospondin-1

Inhibitor of angiogenesis

Transcriptional activation

Apoptosis

Noxa

Control of mitochondrial permeability

Transcriptional activation

Apoptosis

PUMA

Control of mitochondrial permeability

Transcriptional repression

Apoptosis

p3AIP

Control of mitochondrial permeability

Transcriptional repression

Apoptosis

Gadd45

Control of cell cycle in G2

Transcriptional activation

Cell cycle arrest, G2

BTG2

Inhibitor of proliferation

Transcriptional activation

Cell cycle arrest, G1

p21waf-1

Inhibitor of CDK2-4 and 6

Transcriptional activation

Cell cycle arrest, G1 and

G2/M

Cyclin A

Cell-cycle regulation, S phase

Transcriptional repression

Cell cycle arrest, G1/S

13-3-3—s

Control of Cdc25 at G2/M

Transriptional activation

Cell cycle arrest, G2/M

Cyclin G

Cell-cycle regulation

Transcriptional activation

Cell-cycle arrest?

GPx

Glutathione peroxidase

Transcriptional repression

Control of oxidative

stress

NOS2/iNOS

Inducible nitric oxide synthase

Transcriptional repression

Control of oxidative

stress

COX2

Inducible cyclooxygenase

Transcriptional activation

Anti-apoptotic effect?

Pig-1

Galectin-7

Transcriptional activation

Differentiation?

PCNA

Auxilliary subunit of polymerase 8

Transcriptional activation

DNA repair/replication

MSH2

Mismatch DNA Repair

Transcriptional activation

DNA repair

O6MGMT

O6-methylguaninemethyltransferase

Transcriptional activation

DNA repair

HOGG1

O8-deoxyguanosine glycosylase

Activation by protein

DNA repair

binding

RPA

Replication protein A

Inhibition by protein

DNA repair/replication

binding

ERCC2/ERCC3

Helicases, TFIIH complex

Activation by protein

DNA repair/

binding

transcription

P53RR2

Ribonucleotide reductase homolog

Transcriptional activation

DNA repair?

TBP

TATA box-binding protein

Inhibition by protein

Inhibition of

binding

transcription

Mdm-2

Oncogene

Transcriptional activation

Repression of p53

MDR-1

Multidrug resistance

Transcriptional repression

Resistance to

chemotherapy

co-activators p300/CBP. Both of these regulators are involved in differentiation processes. The YY1 (Ying-Yang 1) protein is a transcription factor that plays a role in bone morphogenesis and acts as a suppressor of p53 activation in response to genotoxic stress (Gronroos etal., 2004). ELL (Eleven nineteen lysine rich leukemia) is a transcription elongation factor which can be rearranged by gene translocation to give rise to the MLL-ELL protein in acute lymphoblastic and myeloid leukemias. Both wild-type ELL and MLL-ELL can suppress normal p53 activity (Wiederschain et al., 2003). This mechanism may explain why these cancers often develop in the presence of wild-type TP53 alleles.

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