Abstract
The tumor suppressor protein p27Kip1 plays a pivotal role in the control of cell growth and metastasis formation.Several studies pointed to different roles for p27Kip1 in the control of Ras induced transformation, although no explanation has been provided to elucidate these differences. We recently demonstrated that p27kip1 regulates H-Ras activity via its interaction with stathmin.Here, using in vitro and in vivo models, we show that p27kip1 is an important regulator of Ras induced transformation. In H-RasV12 transformed cells, p27kip1 suppressed cell proliferation and tumor growth via two distinct mechanisms: 1) inhibition of CDK activity and 2) impairment of MT-destabilizing activity of stathmin. Conversely, in K-Ras4BV12 transformed cells, p27kip1 acted mainly in a CDK-dependent but stathmin-independent manner.Using human cancer-derived cell lines and primary breast and sarcoma samples, we confirmed in human models what we observed in mice.Overall, we highlight a pathway, conserved from mouse to human, important in the regulation of H-Ras oncogenic activity that could have therapeutic and diagnostic implication in patients that may benefit from anti-H-Ras therapies.
Highlights
The tumor suppressor protein p27kip1 was originally identified as a cyclin/CDK inhibitor, in particular of the CDK2-containing complexes[1, 2]
To test if these differences may have any role in cell transformation, we generated and characterized H-RasV12transformed wild type (WT) and p27 knock-out (p27KO) 3T3 fibroblasts [7, 21]
In line with our previous results showing that p27/stathmin interaction modulates H-Ras activity [12] we showed that p27WT but not the p271-170 mutant [7,8,9, 12, 21] reduced ERK1/2 phosphorylation when reintroduced in p27KO cells (Supplementary Figure 2A)
Summary
The tumor suppressor protein p27kip (hereafter p27) was originally identified as a cyclin/CDK inhibitor, in particular of the CDK2-containing complexes[1, 2]. In H-Ras-driven tumorigenesis, such as the MMTV-H-RasV12-induced breast and salivary gland cancers [16] or the DMBA/TPA skin carcinogenesis model [17], p27 acts as a classical tumor suppressor gene and loss of one p27 allele does not result in enhanced tumor growth. In these settings, many of the H-RasV12/ p27 null tumors displayed features characteristic of highly aggressive tumors [16]. It has been postulated that p27 controls cell H-RasV12-driven transformation via the inhibition of the cyclin/CDK/RB pathway and via RB-independent pathways [18]
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