The MDM2 and MDMX (also known as HDMX and MDM4) proteins are deregulated in many human cancers and exert their oncogenic activity predominantly by inhibiting the p53 tumour suppressor. However, the MDM proteins modulate and respond to many other signalling networks in which they are embedded. Recent mechanistic studies and animal models have demonstrated how functional interactions in these networks are crucial for maintaining normal tissue homeostasis, and for determining responses to oncogenic and therapeutic challenges. This Review highlights the progress made and pitfalls encountered as the field continues to search for MDM-targeted antitumour agents.

/pdf/mdm2-mdmx-and-p53-in-oncogenesis-and-cancer-therapy-fq03b3bj72.pdf

MDM2, MDMX and p53 in oncogenesis and cancer therapy.

https://www.cell.com/current-biology/pdf/S0960-9822(10)00076-X.pdf

Mechanisms of Chromosomal Instability

Kinesins are a family of molecular motors that travel unidirectionally along microtubule tracks to fulfil their many roles in intracellular transport or cell division. Over the past few years kinesins that are involved in mitosis have emerged as potential targets for cancer drug development. Several compounds that inhibit two mitotic kinesins (EG5 (also known as KIF11) and centromere-associated protein E (CENPE)) have entered Phase I and II clinical trials either as monotherapies or in combination with other drugs. Additional mitotic kinesins are currently being validated as drug targets, raising the possibility that the range of kinesin-based drug targets may expand in the future.

Kinesins and cancer

Centrioles are conserved microtubule-based organelles that form the core of the centrosome and act as templates for the formation of cilia and flagella. Centrioles have important roles in most microtubule-related processes, including motility, cell division and cell signalling. To coordinate these diverse cellular processes, centriole number must be tightly controlled. In cycling cells, one new centriole is formed next to each pre-existing centriole in every cell cycle. Advances in imaging, proteomics, structural biology and genome editing have revealed new insights into centriole biogenesis, how centriole numbers are controlled and how alterations in these processes contribute to diseases such as cancer and neurodevelopmental disorders. Moreover, recent work has uncovered the existence of surveillance pathways that limit the proliferation of cells with numerical centriole aberrations. Owing to this progress, we now have a better understanding of the molecular mechanisms governing centriole biogenesis, opening up new possibilities for targeting these pathways in the context of human disease.

Once and only once: mechanisms of centriole duplication and their deregulation in disease

Centrosome amplification is a hallmark of cancer. However, despite significant progress in recent years, we are still far from understanding how centrosome amplification affects tumorigenesis. Boveri's hypothesis formulated more than 100 years ago was that aneuploidy induced by centrosome amplification promoted tumorigenesis. Although the hypothesis remains appealing 100 years later, it is also clear that the role of centrosome amplification in cancer is more complex than initially thought. Here, we review how centrosome abnormalities are generated in cancer and the mechanisms cells employ to adapt to centrosome amplification, in particular centrosome clustering. We discuss the different mechanisms by which centrosome amplification could contribute to tumour progression and the new advances in the development of therapies that target cells with extra centrosomes.

https://royalsocietypublishing.org/doi/pdf/10.1098/rstb.2013.0467

Causes and consequences of centrosome abnormalities in cancer

We tested whether cleavage failure as a transient event establishes an incidence of centrosome amplification in cell populations. Five rounds of ∼30% cytochalasin-induced cleavage failure in untransformed human cell cultures did not establish centrosome amplification in the short or long terms. The progeny of binucleate cells progressively dropped out of the cell cycle and expressed p53/p21, and none divided a fourth time. We also tested whether cleavage failure established centrosome amplification in transformed cell populations. Tetraploid HCT116 p53−/− cells eventually all failed cleavage repeatedly and ceased proliferating. HeLa cells all died or arrested within four cell cycles. Chinese hamster ovary cells proliferated after cleavage failure, but five rounds of induced cleavage failure produced a modest increase in the incidence of centrosome amplification in the short term, which did not rise with more cycles of cleavage failure. This incidence dropped to close to control values in the long term despite a 2–6% rate of spontaneous cleavage failure in the progeny of tetraploid cells.

/pdf/repeated-cleavage-failure-does-not-establish-centrosome-1ifvyzdfuu.pdf

Repeated cleavage failure does not establish centrosome amplification in untransformed human cells

The cellular homologues Mdm2 and MdmX play critical roles in regulating the activity of the p53 tumor suppressor in damaged and non-damaged cells and during development in mice. Recently, we have utilized genetically defined primary cells and mice to reveal that endogenous levels of MdmX can also suppress multipolar mitosis and transformation in hyperploid p53-deficient cells and tumorigenesis in p53-deficient mice. These MdmX functions are not shared by Mdm2, and are distinct from the well-established ability of MdmX to complex with and inhibit p53 activity. Here we discuss some of the ramifications of MdmX loss in p53-deficient cells and mice, and we explore further the fate of MdmX/p53-double null embryonic fibroblasts undergoing multi-polar cell division using time-lapse video microscopy. We also discuss the relationship between chromosomal loss, cell proliferation, and the tumorigenic potential of p53-deficient cells lacking MdmX.

MdmX regulates transformation and chromosomal stability in p53-deficient cells.

The MDMX (MDM4) oncogene is amplified or overexpressed in a significant percentage of human tumors. MDMX is thought to function as an oncoprotein by binding p53 tumor suppressor protein to inhibit p53-mediated transcription, and by complexing with MDM2 oncoprotein to promote MDM2-mediated degradation of p53. However, down-regulation or loss of functional MDMX has also been observed in a variety of human tumors that are mutated for p53, often correlating with more aggressive cancers and a worse patient prognosis. We have previously reported that endogenous levels of MdmX can suppress proliferation and promote pseudo-bipolar mitosis in primary and tumor cells derived from p53-deficient mice, and that MdmX-p53 double deficient mice succumb to spontaneously formed tumors more rapidly than p53-deficient mice. These results suggest that the MdmX oncoprotein may act as a tumor-suppressor in cancers with compromised p53 function. By using orthotopic transplantation and lung colonization assays in mice we now establish a p53-independent anti-oncogenic role for MdmX in tumor progression. We also demonstrate that the roles of MdmX in genome stability and in proliferation are two distinct functions encoded by the separate MdmX protein domains. The central Zn-finger domain suppresses multipolar mitosis and chromosome loss, whereas the carboxy-terminal RING domain suppresses proliferation of p53-deficient cells. Furthermore, we determine that it is the maintenance of genome stability that underlies MdmX role in suppression of tumorigenesis in hyperploid p53 mutant tumors. Our results offer a rationale for the increased metastatic potential of p53 mutant human cancers with aberrant MdmX function and provide a caveat for the application of anti-MdmX treatment of tumors with compromised p53 activity.

/pdf/the-zn-finger-domain-of-mdmx-suppresses-cancer-progression-m7l3t2gsau.pdf

Anna Krzywicka-Racka

Papers

Repeated cleavage failure does not establish centrosome amplification in untransformed human cells

MdmX regulates transformation and chromosomal stability in p53-deficient cells.

The Zn-finger domain of MdmX suppresses cancer progression by promoting genome stability in p53-mutant cells