Polyploid cells, which contain multiple copies of the typically diploid genome, are widespread in plants and animals. Polyploidization can be developmentally programmed or stress induced, and arises from either cell-cell fusion or a process known as endoreplication, in which cells replicate their DNA but either fail to complete cytokinesis or to progress through M phase entirely. Polyploidization offers cells several potential fitness benefits, including the ability to increase cell size and biomass production without disrupting cell and tissue structure, and allowing improved cell longevity through higher tolerance to genomic stress and apoptotic signals. Accordingly, recent studies have uncovered crucial roles for polyploidization in compensatory cell growth during tissue regeneration in the heart, liver, epidermis and intestine. Here, we review current knowledge of the molecular pathways that generate polyploidy and discuss how polyploidization is used in tissue repair and regeneration.

Significance: Here, we explore a mechanism wherein the growth signaling-dependent translation of mRNA encoding a cell cycle regulatory factor limits rates of cell proliferation. An essential cell cycle transcription factor, E2F1, was found to be post-transcriptionally regulated by TOR and EGFR signaling, and thus served as a candidate growth sensor for this study. Using expression of green fluorescent protein (GFP)-E2F1 transgenes with alterations within the E2f1 5′ untranslated region (UTR), we altered the translation of GFP-E2F1 and changed cell proliferation rates accordingly. Further, we found that 5′UTR upstream open reading frames are TOR-sensitive regulatory components of E2f1 translation. Our observations indicate that growth signaling dependent protein translation is an important regulator of cell proliferation.

Proliferative and endoreduplicative cell cycles are used to variable extents during the ontogeny of individual organisms and in different evolutionary lineages. Chordate growth and development is typically dominated by proliferative cycles, but the urochordate, Oikopleura dioica, has systemically elaborated a number of endocycling modes to support rapid development and growth in an extraordinarily short chordate life cycle. Here, we identify the O. dioica cyclin and cyclin-dependent kinase (CDK) complements and assess their deployment with respect to mitotic, meiotic, and endoreduplicative life cycle phases. Oikopleura dioica's "transcriptional" cyclin and CDK complements are similar to other complex invertebrates, whereas both the "cell cycle" cyclin and CDK complements display astonishing amplifications centered on the cyclin D, cyclin B, and CDK1 families. Somatic endocycles in O. dioica involve downregulation of cyclins B and A, as in other endocycle model systems, but are also characterized by overlapping expression of an array of cyclin D isoforms. Amplification of the mitotic CDK1 family to five paralogs, which continue to be expressed in endocycling phases, is unexpected as suppression of CDK1 activity is central to endocycle transitions in Drosophila and mammals. This amplification is unique among metazoans, and substitutions in odCDK1 paralogs in the nearly invariant cyclin interaction PSTAIRE helix show striking parallels to those in the only other known eukaryotic CDK1 paralogs, plant CDKA and CDKB. As plant CDK1 paralogs exhibit an expanded repertoire of cyclin partners, including cyclin D, the evolutionary coexpansion of odCDK1 and odCyclin D families suggests that multiple CDK1-cyclin D complexes may modulate spatiotemporal control of kinase activity and substrate specificity in diverse cell cycle variants.

The murine double minute 2 (MDM2) is an oncogene and a negative regulator of the tumor suppressor protein p53. MDM2 is known to be amplified in numerous human cancers, and upregulation of MDM2 is considered to be an alternative mechanism of p53 inactivation. The presence of many splice variants of MDM2 has been observed in both normal tissues and malignant cells; however their impact and functional properties in response to chemotherapy treatment are not fully understood. Here, we investigate the biological effects of three widely expressed alternatively spliced variants of MDM2; MDM2-A, MDM2-B and MDM2-C, both in unstressed MCF-7 breast cancer cells and in cells subjected to chemotherapy. We assessed protein stability, subcellular localization and induction of downstream genes known to be regulated by the MDM2-network, as well as impact on cellular endpoints, such as apoptosis, cell cycle arrest and senescence. We found both the splice variants MDM2-B and -C, to have a much longer half-life than MDM2 full-length (FL) protein after chemotherapy treatment indicating that, under stressed conditions, the regulation of degradation of these two variants differs from that of MDM2-FL. Interestingly, we observed all three splice variants to deviate from MDM2-FL protein with respect to subcellular distribution. Furthermore, while MDM2-A and -B induced the expression of the pro-apoptotic gene PUMA, this effect did not manifest in an increased level of apoptosis. Although MDM2-B induced slight changes in the cell cycle profile, overall, we found the impact of the three MDM2 splice variants on potential cellular endpoints upon doxorubicin treatment to be limited.

Cyclin-dependent kinases (CDKs) are central regulators of eukaryotic cell cycle progression. In contrast to interphase CDKs, the mitotic phase CDK1 is the only CDK capable of driving the entire cell cycle and it can do so from yeast to mammals. Interestingly, plants and the marine chordate, Oikopleura dioica, possess paralogs of the highly conserved CDK1 regulator. However, whereas in plants the 2 CDK1 paralogs replace interphase CDK functions, O. dioica has a full complement of interphase CDKs in addition to its 5 odCDK1 paralogs. Here we show specific sub-functionalization of odCDK1 paralogs during oogenesis. Differential spatiotemporal dynamics of the odCDK1a, d and e paralogs and the meiotic polo-like kinase 1 (Plk1) and aurora kinase determine the subset of meiotic nuclei in prophase I arrest that will seed growing oocytes and complete meiosis. Whereas we find odCDK1e to be non-essential, knockdown of the odCDK1a paralog resulted in the spawning of non-viable oocytes of reduced size. Knockdown of odCDK1d also resulted in the spawning of non-viable oocytes. In this case, the oocytes were of normal size, but were unable to extrude polar bodies upon exposure to sperm, because they were unable to resume meiosis from prophase I arrest, a classical function of the sole CDK1 during meiosis in other organisms. Thus, we reveal specific sub-functionalization of CDK1 paralogs, during the meiotic oogenic program.