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PERSPECTIVE

Duality of p27^Kip1 function in tumorigenesis

¹ Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA; ² Children’s Hospital Stem Cell Program and Department of Genetics, Harvard Medical School and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA

In this issue of Genes & Development, Besson et al. (2007) report phenotypic characteristics of a novel knock-in mouse strain expressing a mutant allele of the cell cycle inhibitor p27^Kip1 that has both common and unique features when compared with a null allele. The new studies provide the first direct in vivo evidence that in addition to its role as a tumor suppressor, p27^Kip1 also functions as an oncogene. The work also suggests that p27^Kip1 oncogenic activity leads to aberrant stem and progenitor cell expansion in the lung and retina, respectively. Thus, p27^Kip1’s new "dark side" may serve an oncogenic function that operates in less specialized cell types to influence tumorigenesis.

	The ‘good’ side of p27Kip1 function

Top The 'good' side of... p27Kip1 as an oncogene p27Kip1 regulation of stem... Using cell cycle inhibitor... References

 
The progression of cells through the cell cycle is driven by enzymatic complexes composed of cyclins and their catalytic partners, cyclin-dependent kinases (CDKs) (Sherr and Roberts 1999). When p27^Kip1 was originally cloned, it was thought to act as an inhibitor of cyclin–CDK complexes (Polyak et al. 1994a, b; Toyoshima and Hunter 1994). However, it soon became obvious that the picture was not so simple, as evidence for an additional function for p27^Kip1 was provided by the observations that this cell cycle inhibitor also serves as an essential assembly factor for cyclin D–CDK4 and cyclin D–CDK6 complexes (LaBaer et al. 1997; Cheng et al. 1999). More recent studies revealed that p27^Kip1 plays additional, cell cycle-independent roles. The full repertoire of these functions is only beginning to be appreciated (Fig. 1). So far, these novel functions include regulation of the actin cytoskeleton and cell migration through modulation of RhoA activity (McAllister et al. 2003; Besson et al. 2004; Wu et al. 2006), as well as promoting neuronal differentiation by stabilizing Neurogenin-2 protein (Nguyen et al. 2006).

View larger version (35K): [in this window] [in a new window]   Figure 1. Model of the roles of p27Kip1. (Left) p27Kip1 affects cell cycle progression via interaction with cyclin–CDK complexes and has also been shown to have cell cycle-independent roles such as regulating RhoA activity. (Right) The work of Besson et al. (2007) suggests that p27Kip1 activity related to cell cycle regulation may be more relevant to its role as a tumor suppressor, whereas p27Kip1 also has cyclin–CDK-independent oncogenic activity. Whether the tumor-suppressing or oncogenic activity of p27Kip1 can be assigned strictly to the pathways depicted or compartmentalized based on location in the nucleus or cytoplasm as shown still remains to be determined in detail.

	p27Kip1 as an oncogene

Top The 'good' side of... p27Kip1 as an oncogene p27Kip1 regulation of stem... Using cell cycle inhibitor... References

 
A number of perplexing observations regarding p27^Kip1 activity in murine and human patients appear to contradict the expected role of a tumor suppressor. Although human cancers often express very low levels of p27^Kip1, the homozygous loss of p27^Kip1 is extremely rare. p27^Kip1+/– animals were more susceptible to mammary and prostate tumors than p27^Kip1-null mice, suggesting an active contribution of the intact wild-type p27^Kip1 allele in tumorigenesis (Muraoka et al. 2002; Gao et al. 2004). Lastly, a correlation between poor prognosis and cytoplasmic localization of p27^Kip1 in human tumors suggests an active tumor-promoting function of p27^Kip1 in the cytoplasm (Slingerland and Pagano 2000). These findings have led to the hypothesis that p27^Kip1 has an additional, oncogenic function.

The study by Besson et al. (2007) tested the contribution of CDK-independent functions of p27^Kip1 by analyzing knock-in mice expressing mutant p27^Kip1 (p27^CK–) that is unable to inhibit cyclin–CDK complexes. One might expect that the phenotype of the homozygous p27^CK–/CK– mice would resemble that of p27^Kip1-null animals. This is true to a certain extent, as p27^CK–/CK– mice displayed organomegaly and spontaneous pituitary tumor development, like the original p27^Kip1-null mice. Very unexpectedly, however, Besson et al. (2007) found that p27^CK–/CK– mice also developed a whole range of hyperplastic and neoplastic lesions, including lung adenocarcinomas. This truly stunning observation indicates that the loss of CDK-inhibitory activity unmasks evidence for the oncogenic function of p27^Kip1. A similar phenotype arose in p27^CK–/+ mice, although at a longer latency. Importantly, no loss of heterozygosity was observed in tumors from these mice, adding weight to the hypothesis that this work uncovers an oncogenic role for p27^Kip1. One potential caveat of this work that should also be noted is that, in some contexts, the levels of p27^Kip1 appear elevated compared with wild-type tissue. Thus, it cannot be formally ruled out that some aspects of the phenotype of p27^CK– mice are not due to subtle overexpression.

At present, we can only speculate as to the mechanistic basis for p27^Kip1Kip1 oncogenicity. In human cancer cells, cytoplasmic localization of p27^Kip1Kip1 was shown to correlate with high tumor grade and poor prognosis (Slingerland and Pagano 2000). Intriguingly, the p27^CK– mutant also localizes to the cytoplasm, suggesting that a cytoplasmic function might mediate the oncogenic effect (Fig. 1). However, the p27^CK– protein is not exclusively located in the cytoplasm; future studies that include restriction of p27^Kip1 to particular cellular compartments will likely be key for understanding the mechanism of p27^Kip1 oncogenic function. Of note, p21^Cip1, another cyclin-dependent kinase inhibitor, also exhibits cytoplasmic functions that are likely to be oncogenic (Coqueret 2003), although the formal demonstration for such activity in vivo remains to be seen. Therefore, the work of Besson et al. (2007) may provide the first evidence for similar cytoplasmic-based oncogenic activity of multiple CDK inhibitors. An extensive discussion of the potential effect of p27^Kip1 oncogenic activity via RhoA was provided by Besson et al. (2007) , and since the phenotypes observed in p27^CK– mice in this study were highlighted by their comparison with p27^Kip1-null animals, future comparisons with other p27^Kip1 point mutants that selectively inhibit RhoA pathway alterations, for example, could clarify the CDK-independent functions of p27^Kip1 in tumorigenesis.

	p27Kip1 regulation of stem and progenitor cells

Top The 'good' side of... p27Kip1 as an oncogene p27Kip1 regulation of stem... Using cell cycle inhibitor... References

 
Coupled with oncogenic activity, Besson et al. (2007) reported an increased pool of bronchioalveolar stem cells (BASCs) in p27^CK– mice, suggesting that p27^Kip1 acts within lung stem cells. Cells with both the alveolar marker SPC and the bronchiolar cell marker CC10, which we previously defined as BASCs (Kim et al. 2005), were more abundant in p27^CK– lungs compared with wild-type lungs. It remains to be confirmed whether BASCs from p27^CK– mice have altered stem cell characteristics; ex vivo analysis of the effect of p27^Kip1 activity on BASC self-renewal and differentiation will be informative. Importantly, it appears that the bronchiolar Clara cells, in addition to BASCs, are also stimulated to enter the cell cycle in the presence of the p27^CK– allele. Therefore, it is not apparent whether p27^CK– exerts its effects specifically on BASCs, or rather on multiple types of lung epithelial cells. Adding to the likely complex nature of p27^CK– effects in lung, these mutant mice also developed desquamative interstitial pneumonitis, characterized by an influx of macrophages, neutrophils, and infiltrating lymphocytes that was often difficult to distinguish from tumorigenic lesions. Given this dramatic inflammatory response, it will be of note to determine whether the observed expansion of BASCs or other lung epithelial cells is attributable to signals from inflammatory cells or a cell-autonomous effect.

It is possible that the bulk of p27^Kip1 activity, both cyclin-dependent and putative oncogenic activity, has its readout in progenitor cell populations, rather than specifically in stem cells. Pax6-, Chx10-, and BrdU-positive retinal cells were present in increased numbers in the p27^CK– retina, suggesting an enhanced progenitor phenotype. Besson et al. (2007) note several other tissue-specific progenitor cell types, rather than stem cells, which may be affected by p27^Kip1 function; committed progenitors in the hematopoietic and glial lineages were increased in p27^Kip1–/– mice, whereas hematopoietic stem cells were not (Cheng and Scadden 2002). In fact, members of both the INK4 and CIP/KIP families of CDK inhibitors have long been implicated in the coordination of cell cycle withdrawal and initiation of differentiation in various cell types. Levels of p27^Kip1 in differentiated, nonproliferating tissues are often increased relative to their more immature counterparts (De Clercq and Inze 2006), as has been observed in intestinal epithelial stem/progenitor cells (Quaroni et al. 2000), chondrocytes (Yeh et al. 2007), neuronal progenitors (Nguyen et al. 2006), as well as in ES cells (Egozi et al. 2007). In addition, p27^Kip1 frequently exhibits reduced expression in more poorly differentiated, high-grade tumors (Tsihlias et al. 1999). Interestingly, the ability of p27^Kip1 to promote myogenic and neuronal differentiation in Xenopus, via regulation of the transcription factors MyoD and neurogenin, respectively, is CDK independent (Vernon and Philpott 2003; Vernon et al. 2003). The role of p27^Kip1 in specific cell subsets within given tissues will certainly be worked out with further studies.

As for the oncogenic activity of p27^Kip1, its precise molecular mechanisms in stem or progenitor cell regulation are also largely unknown. Interestingly, RhoA inhibition in hematopoietic stem and progenitor cells lead to increased engraftment and self-renewal (Ghiaur et al. 2006). As Besson et al. (2007) hypothesize that RhoA deregulation is involved in the mechanisms of p27^CK– phenotype, the similar phenotypes of p27^Kip1 and RhoA abrogation in stem or progenitor cells are intriguing. No apparent migratory activity of BASCs was noted in p27^CK– mice as might be expected for RhoA misregulation, but proliferative retinal progenitors were in ectopic locations, possibly suggesting a tissue-specific effect on cell migration and distinct mechanisms downstream from p27^Kip1 in diverse tissues.

	Using cell cycle inhibitor analysis to uncover the origins of cancer

Top The 'good' side of... p27Kip1 as an oncogene p27Kip1 regulation of stem... Using cell cycle inhibitor... References

 
The lung phenotype reported by Besson et. al. (2007), together with recent reports analyzing several other genetic pathways, further support previous studies that expansion of an adult stem cell population in the lung leads to the development of non-small-cell lung cancer. p27^CK–, p38MAPK deficiency (Ventura et al. 2007), and p18^Ink4c deficiency (Pei et al. 2007) all appear to increase the number of BASCs and enhance susceptibility to lung tumorigenesis (along with other unknown components or when analyzed directly with activation of oncogenic K-ras) (Fig. 2). The abundance of proliferative retinal progenitors in p27^CK– mice does not lead to retinoblastomas, and rather seems to activate an apoptotic response. The onset of lung tumorigenesis in p18^–/– and p27^CK– mice occurs in aged adults, and even though BASC expansion in mutant lungs is reportedly widespread, these animals only develop one or two lung tumors. Thus, expansion of stem and progenitor cells is clearly not sufficient for the development of frank carcinomas in the lung or retinal tumors, and other genetic or epigenetic events likely cooperate with, for example, oncogenic p27^Kip1, to allow for tumor formation. Again, as above, it is not yet clear that these pathways only affect stem or progenitor cells, and so future studies allowing cell-type-specific genetic manipulation will be needed to truly determine which cell types give rise to cancer in the lung and other organs.

View larger version (37K): [in this window] [in a new window]   Figure 2. Cartoon representation of effects on lung stem cell number and tumorigenesis. (Top) In the normal lung, BASCs are present in low abundance in the bronchioalveolar niche, where it is hypothesized they can differentiate into Clara cells that line the bronchioles or the alveolar epithelial type 1 and 2 cells (AT1/2) that form the lung alveolar region. (Bottom) Recent findings indicate that abrogation of a number of pathways similarly leads to an increase in BASC numbers and enhanced lung cancer susceptibility. The route by which BASC expansion might lead to lung cancer formation and the direct impact of these mutations on stem cell function are open questions.

	Footnotes

 
³ Corresponding author.

E-MAIL Carla.kim{at}childrens.harvard.edu; FAX (617) 730-0222.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1583207

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This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sicinski, P. Articles by Kim, C. Search for Related Content PubMed PubMed Citation Articles by Sicinski, P. Articles by Kim, C. Related Content Cancer and Disease Models Related Article Social Bookmarking                   What's this?