Different cooperating effect of p21 or p27 deficiency in combination with INK4a/ARF deletion in mice

Abstract

The control exerted by the INK4a/ARF locus on cellular proliferation is crucial to restrict tumor development. In agreement with this, mice with defects in this locus are highly tumor prone. However, the potential contribution of other pathways in modulating tumorigenesis in the absence of INK4a/ARF is largely unexplored. In the present study, we investigated the consequences of the combined loss of either of two cyclin-dependent kinase inhibitors, p21 and p27, in cooperation with deletion of the INK4a/ARF locus. Our results show a clear differential effect in tumorigenesis depending on the CKI that is absent. The absence of p21 produced no overt alteration of the lifespan of the INK4a/ARF-null mice, although it modified their tumor spectrum, causing a significant increase in the incidence of fibrosarcomas and the appearance of a small number of rhabdomyosarcomas. In contrast, deficiency of p27 resulted in a significant increase in lethality due to accelerated tumor development, especially in the case of T-cell lymphomas. Finally, combined deficiency of INK4a/ARF and p27 resulted in a significant increase in the number of metastatic tumors. These results demonstrate genetically the oncogenic cooperation between defects on INK4a/ ARF and p27, which are common alterations in human cancer.

Genetic dissection of the role of p21Cip1/Waf1 in p53-mediated tumour suppression

“…Thus, p21-deficient cells show a defective G 1 checkpoint and do not arrest upon DNA damage and other insults (Brugarolas et al, 1995;Deng et al, 1995). Furthermore, p21-null animals develop tumours spontaneously (Martin-Caballero et al, 2001), present increased tumour susceptibility using chemical carcinogenesis (Philipp et al, 1999;Topley et al, 1999;Weinberg et al, 1999;Jackson et al, 2002;Jackson et al, 2003;Poole et al, 2004), and exacerbate the tumour-prone phenotype of other mouse models (Brugarolas et al, 1998;Adnane et al, 2000;Franklin et al, 2000;Yang et al, 2001Yang et al, , 2005Bearss et al, 2002;Martin-Caballero et al, 2004). In contrast to this, p21-deficiency does not accelerate tumorigenesis in the absence of p53 (De la Cueva et al, 2006), which suggests that the role of p21 in tumour suppression is dependent on p53.…”

Combined loss of p21waf1/cip1 and p27kip1 enhances tumorigenesis in mice

“…27 Therefore, there are multiple evidences for the role that either p21 or p27 has in tumorigenesis, alone or in combination with other tumor suppressors and oncogenes. 14,[28][29][30][31] In addition, CDK-independent functions have been described for p21 and p27, highlighting their role as oncogenes or in cellular stress in different tissues, implicating p21 and p27 as possible therapeutic targets in some processes. 32,33 Up to now, no studies have been described using a doublenull murine model for p21 and p27.…”

“…In p18 Ink4c -p21 doublenull mice, the presence of p21 accelerates the incidence of pituitary adenomas and lung bronchoalveolar adenomas, 12 and in p53-deficient mice increases the frequency of lymphomas and sarcomas. 13 In p15 Ink4a -null mice, the lack of p21 increases the number of fibrosarcomas and rhabdomyosarcomas 14 and, combined with Atm deficiency, enhances the frequency of sarcomas, myeloid leukemias, hepatomas and teratomas. 15 p27 Kip1 (hereafter referred to as p27), another Cip/Kip family member, has a significant role on cell cycle regulation based on its potent inhibitory activity of CDK2-cyclin E, which results in G1 arrest.…”

Conquering the complexity of p53

“…This idea results from several different lines of evidence. First, original reports of mice deficient in p21 indicated that these mice had a compromised G1 arrest response but did not reproduce the cancer-prone phenotype of p53-null mice [6][7][8] . Second, ectopic cell cycle entry caused by inactivation of retinoblastoma (Rb) function in the mouse by mutation 9 or viral oncoprotein sequestration 10 engenders a p53-dependent apoptotic response.…”