Mini-ReviewOncogenic functions of tumour suppressor p21Waf1/Cip1/Sdi1: association with cell senescence and tumour-promoting activities of stromal fibroblasts
Section snippets
p21 and its molecular interactions
p21Waf1/Cip1/Sdi1 is the first identified inhibitor of cyclin/cyclin-dependent kinase (CDK) complexes, which regulate transitions between different phases of the cell cycle. p21 was independently isolated as a CDK-binding protein [1] and as a growth-inhibitory gene which is upregulated by wild-type p53 [2] or overexpressed in senescent fibroblasts [3]. Although many other CDK inhibitors have since been discovered [4], p21 appears to be the only inhibitor capable of interacting with essentially
p21 induction in the programs of damage response and cell senescence
p21 expression is increased by different cell types in response to a variety of stressful stimuli, including DNA-damaging drugs or ionizing radiation, agents affecting DNA replication (mimosine) or mitosis (taxol), TGFβ, differentiating agents or oncogenic Ras. The responses to some of these factors (e.g. DNA damage or mutant RAS) are mediated primarily through transcriptional activation of the p21 gene by p53. Other p21 inducers, such as TGFβ or mimosine, induce p21 in a p53-independent manner
Role of p21 in cell cycle arrest and maintenance of genomic stability
Ectopic expression of p21 arrests the cell cycle either in G1 or in both G1 and G2, depending on the cell type [37]. While p21-induced G1 arrest can be readily explained by direct inhibition of G1-specific cyclin/CDK complexes, the mechanism of p21-induced G2 arrest is less obvious. As stated above, inhibition of the CDC2/cyclin B1 complex by p21 binding may require higher than physiological doses of p21, but p21 was found to inhibit the activating phosphorylation of CDC2 at Thr161 [7]. p21
Effects of p21 knockout on carcinogenesis in the mouse
The role of p21 in carcinogenesis has been investigated in mouse models through gene knockout studies. In light of the established role of p21 in cell cycle arrest, it was a big surprise that p21−/− mice were initially reported to remain tumour-free until at least 7 months of age [42]. Recently, however, Martin-Caballero et al. [51] showed that p21−/− mice develop spontaneous tumours at an average age of 16 months, whereas control animals remain tumour-free for over 2 years. The tumours of
p21 in human cancer
Several p21 mutations have been reported in human cancers [59], [60], [61], [62], [63], and some of these mutations were shown to abrogate p21 activity as a CDK inhibitor [64]. Nevertheless, the overall conclusion from various large-scale studies that have searched for p21 mutations in human cancer has been that p21 mutations are exceedingly rare [65], [66], [67]. This paucity of mutations sets p21 at a striking contrast to other tumour suppressors, such as p53 or p16, which act in the same
Destabilizing effects of p21 induction on mitosis and genome stability
How could p21, one of the principal checkpoint control proteins, contribute to carcinogenesis and tumour progression? As mentioned above, lower levels of p21 promote the assembly of active Cyclin D-CDK4/6 complexes, suggesting that p21 may potentially promote cell growth [5]. Nevertheless, all the studies on p21 knockout or overexpression support the role of p21 as an inducer of cell cycle arrest but not as a positive regulator of cell cycle progression. A possible exception is the work of
p21 as an inhibitor of apoptosis
Probably the best documented oncogenic function of p21 is its ability to protect cells from apoptosis [8]. Importantly, p21 is cleaved by caspase 3 at the onset of apoptosis, losing its apoptosis-suppressing activity [96]. The anti-apoptotic function of p21 can explain why p21 knockout decreases the rate of radiation-induced tumourigenesis in p21 knockout mice [51] and increases the sensitivity to radiation-induced apoptosis in ATM−/− mouse cells [57].
Many studies on the role of p21 in
Paracrine effects of p21 induction: parallels with cell senescence and tumour-promoting functions of stromal fibroblasts
Additional biological functions of p21 have been revealed by cDNA microarray analysis of the effects of p21 on gene expression in HT1080 fibrosarcoma cells [15]. p21 expression, which induces a senescent phenotype in this cell line, was found to upregulate a large group of genes encoding extracellular matrix components and other secreted proteins, many of which have been associated with cell senescence and organism aging. p21-inducible genes include a group of anti-apoptotic and mitogenic
Effects of p21 on stress sensitivity and age-related diseases
p21 induction activates not only tumour-promoting factors but also a number of genes associated with different aspects of aging [15]. One of these genes is p66Shc, a mediator of oxidative stress. The knockout of p66 expands the lifespan of mice by about 30% and greatly increases in vivo survival of a toxin (paraquat) [128]. Remarkably, p21 knockout mice also show much improved survival of toxic treatment, in this case ionizing radiation [51]. Radiation survival of p21−/− mice has been
p21 and p21-mediated pathways as potential targets for therapeutic intervention
As described above, the expression of p21, which is induced in response to many different forms of stress, has pleiotropic effects that are not directly related to the role of p21 in cell cycle arrest. These effects, which include genome destabilization, prevention of apoptosis, overexpression of secreted anti-apoptotic and mitogenic factors, and activation of genes involved in age-related diseases, may contribute to tumour progression, carcinogenesis, and some of the detrimental side effects
Acknowledgements
I thank all the members of our laboratory whose work has been described in this review. The author's studies have been supported by grants R01 CA89636, R01 CA62099 and R37 CA40333 from the U.S. National Cancer Institute.
References (137)
- et al.
WAF1, a potential mediator of p53 tumour suppression
Cell
(1993) - et al.
Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen
Exp. Cell Res.
(1994) - et al.
p21 inhibits thr161 phosphorylation of cdc2 to enforce the G2 DNA damage checkpoint
J. Biol. Chem.
(2000) p21(WAF1/Cip1): more than a break to the cell cycle?
Biochim. Biophys. Acta
(2000)- et al.
Reciprocal regulation via protein-protein interaction between c-Myc and p21(cip1/waf1/sdi1) in DNA replication and transcription
J. Biol. Chem.
(2000) - et al.
Functional interaction of STAT3 transcription factor with the cell cycle inhibitor p21WAF1/CIP1/SDI1
J. Biol. Chem.
(2000) - et al.
Transcriptional regulation of the p21 (WAF1/CIP1)gene
Exp. Cell Res.
(1999) - et al.
p21 (WAF1/CIP1) expression is induced in newly nondividing cells in diverse epithelia and during differentiation of the Caco-2 intestinal cell line
Exp. Cell Res.
(1996) The biology of replicative senescence
Eur. J. Cancer
(1997)- et al.
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Cell
(1997)