p27^Kip1 and STMN1: Partners again?

Orderly progression through the cell cycle is controlled by regulatory complexes which include cyclin-dependent kinases (CDK) and their negative regulators, CDK inhibitors (CKI). p27^Kip1 is one of the major CKI that controls normal cellular proliferation and whose dysregulation has been implicated in malignant transformation¹. In addition to its cell cycle-related function, p27^Kip1 has emerged as a critical regulator of cell motility and migration by influencing the cytoskeleton via direct interaction with actin and/or microtubule (MT)-regulatory proteins.^2,3 Stathmin (STMN1) is a MT destabilizing protein which has been previously identified as a p27^Kip1 binding partner in modulating cell migration in vitro.³

STMN1 is a highly conserved cytoplasmic protein which plays a pivotal role in MT dynamics both in interphase and mitosis.⁴ STMN1 acts as a MT destabilizer by promoting microtubule depolymerization and sequestering tubulin heterodimers thus preventing their polymerization. A tight regulation of STMN1 expression is critical for proper cell cycle progression. Overexpression of STMN1 characterizes a broad range of human malignancies and correlates strongly with advanced disease stages, metastasis and poor prognosis.⁵ While there is convincing evidence for a role of STMN1 up-regulation in maintaining the malignant phenotype, recent observations indicate that this role might not be exclusively related to its MT-regulatory function but to interactions with other molecules which are implicated in human cancer.

This concept is supported by an elegant study by Berton and colleagues describing yet another facet of the functional relationship between p27^Kip1 and STMN.⁶ Given the roles of both proteins in cellular proliferation and building on the original findings of STMN1-p27^Kip1 interaction in vitro,³ the authors interrogated the functional relevance of such interaction in vivo. Utilizing a double knock-out (DKO) mouse model in which both p27^Kip1 and STMN1 were deleted, they demonstrated that p27^Kip1 and STMN1 cooperate in controlling cellular proliferation in vivo. Through carefully designed phenotypical analyses they showed that loss of STMN1 in the p27^Kip1-null background rescued the increased body and organ size that characterizes p27^Kip1KO in mice. Examination of cellular proliferation in DKO mice revealed that suppression of STMN1 prevented cellular proliferation in various tissues, including the retina basal layer, pituitary gland and thymus. More importantly, the development of pituitary adenomas, which occurs upon the sole depletion of p27^Kip1, was prevented when p27^Kip1 and STMN1 were depleted concomitantly. These findings support the idea that, at least in certain cell types, p27^Kip1 and STMN1 may work together to regulate cellular proliferation.

In order to understand the underlying mechanisms of these phenotypical changes, the authors asked if the major CDKs/cyclin complexes are responsible for mediating p27^Kip1 and STMN1interaction in DKO animals. Surprisingly, they found that the absence of STMN1 in p27^Kip1-null context influenced the activity of CDK4/6-cyclin D3 rather than the expected CDK2-cyclin A2 complexes. These findings were further correlated with the gene expression profiles which suggested that p27^Kip1-STMN1 may affect cell cycle by disrupting intracellular signaling cascades triggered by external stimuli (e.g. JAK-STAT, MAPK). These preliminary results should prompt future research to determine if STMN1 phosphorylation status, which is known to drive its cellular activities, is influenced by p27^Kip1 suppression. This would be particularly relevant as STMN1 is a phosphorylation substrate not only for components of the signaling pathways revealed by this study but also for p27^Kip1-regulated CDKs.

The findings reported by Berton et al. represent an important step in understanding the mechanisms by which p27^Kip1 and STMN1 might cooperate in controlling normal and malignant cell proliferation. Yet, more research is needed to provide definitive proof for a direct physical interaction between p27^Kip1 and STMN1 in vivo. The anti-proliferative function of STMN1 inhibition has been widely documented in various systems⁵ which makes it entirely possible that suppression of STMN1would rescue the hyper-proliferative phenotype of the p27^Kip1KO mice through mechanisms independent of its potential relationship with p27^Kip1. Nonetheless, this study opens new lines of investigation that will undoubtedly clarify the precise role of the p27^Kip1-STMN1 regulatory loop in human disease. Intriguingly, increased STMN1 levels were recently shown to correlate with reduced cytoplasmic p27^Kip1 expression in human extrahepatic cholangiocarcinoma (EHCC) and suppression of STMN1 in EHCC cells resulted in accumulation of p27^Kip1 coupled with reduced proliferation.⁷ It is therefore crucial to further define and validate the aberrant p27^Kip1-STMN1 axis in human cancer as it may hold promise for potential therapeutic targeting.