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Maturation promoting factor

Maturation-promoting factor (MPF), also known as M-phase promoting factor, is a universal protein kinase complex in eukaryotic cells that induces entry into the M phase of the cell cycle, specifically driving the G2/M transition to trigger mitosis or meiosis.^[1] It consists of a catalytic subunit, cyclin-dependent kinase 1 (CDK1, formerly Cdc2), bound to a regulatory cyclin B subunit, which together exhibit histone kinase activity essential for nuclear envelope breakdown, chromosome condensation, and spindle assembly.^[2]^[3] MPF was first identified in 1971 through experiments in which cytoplasm from mature Rana pipiens oocytes induced maturation in immature oocytes, revealing a transferable activity independent of new protein synthesis.^[4] Subsequent studies in Xenopus laevis and starfish oocytes confirmed its role as an intracellular regulator, with purification in 1988 identifying the 32-kDa CDK1 and 45-kDa cyclin B components that correlate with MPF activity.^[2]^[5] This discovery laid foundational insights into cell cycle control, linking MPF to the broader cyclin-CDK oscillator mechanism that governs periodic progression through the cell cycle phases.^[3] MPF activity is tightly regulated to ensure precise timing of M-phase entry, primarily through cyclin B accumulation during G2 phase, followed by activating phosphorylation of CDK1 at threonine 161 and inhibitory phosphorylations at tyrosine 15 and threonine 14 that are relieved by Cdc25 phosphatases.^[1] Inactivation occurs via ubiquitin-mediated degradation of cyclin B by the anaphase-promoting complex/cyclosome (APC/C), allowing exit from M phase.^[3] Additional regulators, such as Greatwall kinase, enhance MPF function by inhibiting protein phosphatase 2A-B55 to stabilize CDK1 substrates.^[1] Dysregulation of MPF contributes to cell cycle disorders, including cancer, underscoring its critical role in cellular proliferation and development.^[6]

History and Discovery

Early Observations in Oocyte Maturation

In the 1960s and 1970s, studies on amphibian oocyte maturation shifted from a primary emphasis on hormonal triggers to the recognition of intracellular regulatory factors, particularly in species like the frog Rana pipiens. Early research had established that hormones such as progesterone, released from follicular cells, were essential for initiating maturation in intact oocytes, but experiments involving defolliculation revealed that isolated oocytes could still respond to the hormone, suggesting downstream cytoplasmic mediators.^[7] This transition highlighted the role of oocyte-intrinsic components in controlling nuclear and cytoplasmic changes during meiosis resumption.21002-2) Pioneering experiments by Yoshio Masui and Clement L. Markert in the early 1970s provided direct evidence for such an intracellular factor. Using Rana pipiens oocytes, they demonstrated that cytoplasm extracted from progesterone-treated, maturing oocytes could induce maturation when microinjected into untreated, immature recipient oocytes, even in the absence of exogenous hormones.^[8] This transfer bypassed the need for hormonal stimulation, showing that the inducing activity resided in the donor cytoplasm and was sufficient to trigger the maturation process. These findings, reported in 1971, marked the initial observation of what would later be termed maturation-promoting factor (MPF).^[9] Oocyte maturation in amphibians involves distinct stages, with germinal vesicle breakdown (GVBD) serving as a hallmark event signaling the resumption of meiosis I. GVBD entails the dissolution of the nuclear envelope and the disappearance of the nucleolus within the large germinal vesicle of the prophase-arrested oocyte, leading to chromosome condensation and spindle formation.^[7] In Rana pipiens, progesterone treatment of defolliculated oocytes typically induces GVBD within 8-10 hours, reflecting the activation of intracellular pathways that coordinate these nuclear events with cytoplasmic rearrangements, such as pigment migration and cortex reorganization.^[10] The assay for MPF activity relied on quantitative cytoplasmic transfer experiments, where small volumes (approximately 50-100 nl) of cytoplasm from maturing donor oocytes were injected into immature recipients, and the percentage of induced GVBD was measured as a proxy for activity levels.^[8] This method revealed that MPF-like activity appeared in the cytoplasm shortly after progesterone exposure and could be modulated by inhibitors like cycloheximide, which blocked protein synthesis and thus prevented activity buildup if applied early.^[9] Centrifugation studies further localized the factor to the hyaline region of the ooplasm, confirming its cytoplasmic nature. Later work identified MPF as a protein complex, but these early assays established its phenomenological role in oocyte maturation.^[7]

Identification of the Factor and Key Experiments

The identification of maturation-promoting factor (MPF) as a distinct biochemical entity advanced significantly in the 1980s through collaborative efforts between Yoshio Masui's laboratory, which refined microinjection assays into immature Xenopus laevis oocytes to quantify MPF activity based on germinal vesicle breakdown and maturation progression, and James Maller's laboratory, which utilized protein kinase assays to probe its enzymatic properties. These assays established that MPF induces oocyte maturation with high efficiency, where one unit of activity corresponds to 50% maturation in recipient oocytes, and demonstrated its species-nonspecific nature across amphibian species.^[8]^[11] Early biochemical characterization by Maller's group revealed that MPF activation correlates with a marked increase in protein phosphorylation during oocyte maturation, prompting the hypothesis that MPF functions as a protein kinase or kinase activator; this was confirmed through in vitro phosphorylation assays showing MPF-dependent labeling of oocyte proteins, particularly histones and lamins.90352-6)90251-2) A breakthrough enabling in vitro studies occurred in 1983 when Manfred Lohka, working with Masui, developed cell-free extracts from activated Rana pipiens eggs that recapitulated nuclear remodeling events; these extracts induced pronuclear formation and chromosome condensation in added Xenopus sperm chromatin, providing a system to monitor MPF-driven processes without intact cells. Subsequent refinement by Lohka and Maller in 1985 demonstrated that adding active MPF to interphase extracts triggered nuclear envelope breakdown, premature chromosome condensation, and microtubule spindle assembly, directly linking MPF to mitotic morphology in a cell-free context. Purification efforts culminated in 1988, when Lohka, Hayes, and Maller isolated MPF from mature Xenopus laevis eggs using ammonium sulfate precipitation, ion-exchange chromatography, and gel filtration, yielding a highly active fraction that induced metaphase chromosome formation in cell-free systems; SDS-PAGE analysis revealed two predominant polypeptides of 32 kDa and 45 kDa, with the complex exhibiting histone kinase activity essential for its function. The 32 kDa subunit was a phosphoprotein whose phosphorylation state modulated activity, though its identity as cyclin B was a later clarification tied to parallel discoveries. Initial nomenclature distinguished MPF from the extracellular maturation-inducing steroid progesterone, as microinjection experiments showed MPF resides in oocyte cytoplasm and resists diffusion like small molecules, with activity abolished by proteinase treatment but retained after dialysis, resolving any perceived overlap through direct activity transfer assays. Parallel work by Tim Hunt in 1982 identified periodic 45-50 kDa phosphoproteins in sea urchin eggs whose synthesis and degradation oscillate with cell divisions, providing the conceptual framework that these "cyclins" regulate MPF, later confirmed in Xenopus systems.^[8]90358-9) Cell-free extracts further revealed MPF's dynamic nature, with Gerhart and colleagues demonstrating in 1984 that MPF activity oscillates between high (M-phase-like) and low (interphase-like) states in cycling Xenopus egg extracts, mimicking embryonic cell cycle phases through periodic activation and inactivation.

Naming and Initial Characterization

The term "maturation promoting factor" (MPF) originated from studies on amphibian oocyte maturation in the early 1970s, when Yoshio Masui and Clement Markert demonstrated that a cytoplasmic factor from mature frog eggs could induce germinal vesicle breakdown (GVBD) and meiotic resumption in immature oocytes upon microinjection. This factor was initially identified in Rana pipiens oocytes, where it was shown to act independently of the nucleus, highlighting its cytoplasmic nature and role in triggering meiotic progression without requiring ongoing protein synthesis after initial activation. By the mid-1970s, similar activities were observed in other species, leading to the recognition that MPF could also promote mitotic events in cleaving embryos, prompting its generalization as "mitosis promoting factor" in somatic cells.^[1] Initial biochemical characterization in the 1980s revealed MPF as a heat-stable activity, resistant to incubation at 42°C for up to 30 minutes, yet sensitive to protease treatment such as pronase, which inactivated it rapidly, indicating a proteinaceous component. Further assays demonstrated that MPF possessed protein kinase activity, particularly toward histone H1, distinguishing it from cAMP-dependent pathways, as its induction by progesterone in oocytes occurred without changes in intracellular cAMP levels, and purified MPF was unaffected by cAMP modulators or the heat-stable inhibitor of cAMP-dependent protein kinase.^[12] Unlike steroid hormone signaling, which acts upstream to initiate maturation, MPF was positioned as a downstream effector that directly drove nuclear envelope breakdown and chromosome condensation. In 1988, the connection between MPF and the cdc2 kinase from fission yeast was established, with William Dunphy and colleagues showing that the Xenopus homolog of cdc2 (p34cdc2) co-purified with MPF activity and exhibited cyclin-dependent kinase properties essential for mitotic entry.^[13] Paul Nurse's parallel work on Schizosaccharomyces pombe cdc2+ further unified these findings, demonstrating that this conserved kinase regulated both G1/S and G2/M transitions across eukaryotes, positioning MPF as the active cyclin B-cdc2 complex central to cell cycle control.^[14] Debates on species-specificity arose in the late 1980s, as initial oocyte studies suggested potential variations, but by 1990, cross-species microinjection experiments confirmed MPF's functional conservation, with starfish and clam MPF inducing GVBD in Xenopus oocytes, and vice versa, extending to both vertebrates and invertebrates. This universality underscored MPF's role as a core regulator beyond amphibian meiosis, resolving earlier concerns about taxon-specific mechanisms.^[3]

Molecular Composition

Core Components

Maturation promoting factor (MPF) is a heterodimeric protein complex composed of cyclin B as the regulatory subunit and cyclin-dependent kinase 1 (CDK1, also known as cdc2) as the catalytic subunit.^[15] This complex forms the core of MPF's ability to drive meiotic and mitotic progression in eukaryotic cells.^[16] Cyclin B, with a molecular weight of approximately 45-55 kDa depending on the isoform and species, serves as the regulatory component that confers substrate specificity and temporal control to the complex.^[17] Among its isoforms, cyclin B1 is the primary form associated with mitosis, where it is synthesized during the G2 phase of the cell cycle through regulated transcription and translation, leading to its accumulation prior to mitotic entry.^[16] In contrast, CDK1, the 34 kDa catalytic subunit, is highly conserved across eukaryotes, from yeast cdc2 homologs to vertebrate forms, enabling its universal role in phosphorylating target proteins to initiate M-phase events.^[18] Prior to complex formation, CDK1 exists as an inactive monomer incapable of significant kinase activity without cyclin binding.^[15] Similarly, cyclin B is inherently unstable on its own and relies on association with CDK1 for functional persistence, as unbound cyclin B is rapidly turned over.^[19] The stoichiometric ratio of the MPF complex is 1:1, with one molecule of cyclin B binding to one molecule of CDK1 to form the active heterodimer.^[15] Cyclin B levels fluctuate cyclically, rising via de novo synthesis in G2 and declining through proteolysis at the end of mitosis, which directly modulates MPF activity.^[16] This composition ensures that MPF activity is tightly coupled to cell cycle progression.

Assembly and Stoichiometry

The assembly of maturation promoting factor (MPF), composed of cyclin B and cyclin-dependent kinase 1 (CDK1), initiates in the late G2 phase through the binding of newly translated cyclin B to CDK1 monomers. This interaction is facilitated by the conserved cyclin box domain in cyclin B, a structural motif that specifically recognizes and docks onto a hydrophobic cleft on the CDK1 surface, inducing conformational changes necessary for complex stability.^[20]^[21] The resulting MPF holoenzyme exhibits a strict equimolar stoichiometry of one cyclin B molecule per CDK1 subunit, ensuring precise kinase activity control; excess unbound cyclin B is rapidly degraded via ubiquitin-mediated proteolysis to prevent aberrant activation.^[22] Prior to full assembly, CDK1 undergoes pre-phosphorylation at threonine 161 (Thr161) by CDK-activating kinase (CAK, typically the CDK7-cyclin H complex), which partially activates the monomer and primes it for cyclin B binding, although full activity requires subsequent dephosphorylation events.^[23] Complex formation peaks immediately before the G2/M transition, accumulating pre-MPF reserves that remain inactive due to inhibitory phosphorylation by Wee1 kinase on CDK1 residues Thr14 and Tyr15, thereby enforcing temporal control until cellular conditions permit mitotic entry.^[24]^[25] This regulated assembly ensures that MPF activation aligns with DNA replication completion and checkpoint satisfaction.^[26]

Structural Features

Cyclin-Dependent Kinase Domain

The cyclin-dependent kinase 1 (CDK1) serves as the catalytic core of maturation promoting factor (MPF), exhibiting a canonical bilobal protein kinase fold that is characteristic of the eukaryotic protein kinase superfamily. This architecture consists of an N-terminal lobe, primarily composed of β-sheets and responsible for nucleotide binding, and a C-terminal lobe, dominated by α-helices and involved in substrate positioning and catalysis. The ATP-binding cleft is located at the interface between these lobes, formed by conserved structural elements such as an extended hairpin from residues 40–46 in the N-lobe, which shapes the active site pocket for ATP coordination.^[27]^[28] A hallmark of CDK1 is the PSTAIRE motif, a conserved sequence (residues 45–51) embedded within the αC-helix of the N-lobe, which contributes to the overall fold stability and serves as a key interface for regulatory interactions. The activation loop, spanning residues 146–173, includes substrate recognition sites that, in the inactive conformation, obstruct access to the active site but can reposition to facilitate phosphotransfer. Critical residues within this domain include Thr14 and Tyr15 in the glycine-rich loop (G-loop) of the N-lobe, which are sites of inhibitory phosphorylation that distort the ATP-binding geometry, and Asp128 in the C-lobe, which acts as the catalytic base to abstract a proton from the substrate's hydroxyl group during phosphate transfer.^[28]^[27]^[29] CDK1 displays high evolutionary conservation across eukaryotes, sharing approximately 65% sequence identity with CDK2 and homology to yeast Cdc28, reflecting its ancient origin as the primordial cell cycle kinase. Despite this homology, CDK1 has specialized for mitotic functions through unique structural features, such as differences in key loops and a disordered activation segment in its monomeric form.^[27]

Cyclin Binding and Conformational Changes

The binding of cyclin B to CDK1, forming the maturation promoting factor (MPF), is mediated by the hydrophobic cyclin box motif within cyclin B, which engages the αC-helix (containing the PSTAIRE sequence) of CDK1 through extensive hydrophobic interactions. This interface, encompassing approximately 1,200 Å² of buried surface area, positions key residues such as Phe153 of CDK1's activation segment into a hydrophobic groove on cyclin B, stabilizing the complex.^[18] The interaction induces a rotation and repositioning of CDK1's T-loop (the activation segment spanning residues 145–171), displacing it from the catalytic cleft and relieving steric hindrance that blocks substrate access in the monomeric CDK1.^[18]^[30] This cyclin B binding triggers a profound conformational shift in CDK1, reorienting the αC-helix and displacing the DFG motif (Asp-Phe-Gly) at the start of the activation segment to form a short β-hairpin structure. The shift stabilizes an open conformation of the ATP-binding site, enhancing nucleotide affinity and enabling proper alignment of catalytic residues. Overall, these changes prime CDK1 for activation by exposing the Thr161 phosphorylation site to CDK-activating kinase (CAK), although the unphosphorylated CDK1-cyclin B complex retains low kinase activity.^[18]^[31] Allosterically, cyclin B binding exposes the Thr161 residue in CDK1's activation segment, positioning it for phosphorylation by CDK-activating kinase (CAK), which inserts into a solvent-filled cleft created by the conformational rearrangement. This exposure is critical, as the T-loop in free CDK1 occludes the site, preventing efficient CAK access.^[18] The resulting Thr161 phosphorylation further rigidifies the activation segment, increasing complex stability.^[18] Insights into these dynamics derive from 1990s X-ray crystal structures, such as that of the CDK2-cyclin A complex at 2.9 Å resolution, which showed cyclin binding causing a ~20° rotation between the N- and C-terminal lobes of the kinase, opening the active site cleft—a conserved mechanism extrapolated to MPF given the structural homology between CDK1-cyclin B and CDK2-cyclin A. Later structures of CDK1-cyclin B confirmed similar lobe reorientation and interface features, albeit with a smaller binding surface due to CDK1-specific twists in the C-helix.^[30]^[18]

Regulation of Activity

Activation Pathways

The activation of maturation promoting factor (MPF), composed of cyclin B and cyclin-dependent kinase 1 (CDK1), involves a series of tightly regulated post-translational modifications that culminate in full enzymatic activity. Upon binding of cyclin B to CDK1, the complex undergoes initial phosphorylation by CDK-activating kinase (CAK), which adds a phosphate group to threonine 161 (Thr161) on the activation loop (T-loop) of CDK1, enhancing its catalytic competence and substrate affinity.^[32] This activating phosphorylation is essential but insufficient on its own, as the cyclin B-CDK1 complex remains inactive due to inhibitory phosphorylations at threonine 14 (Thr14) and tyrosine 15 (Tyr15), introduced by Wee1 and Myt1 kinases during G2 phase to prevent premature mitotic entry.^[33] Full activation requires the removal of these inhibitory phosphates by members of the Cdc25 phosphatase family, particularly Cdc25B and Cdc25C, which dephosphorylate Thr14 and Tyr15 in a stepwise manner at the G2/M transition.^[34] This dephosphorylation is triggered by upstream signals, such as DNA damage checkpoints being satisfied, and initiates a powerful positive feedback loop: newly activated MPF phosphorylates and activates Cdc25 phosphatases while simultaneously inhibiting Wee1 kinase activity, thereby accelerating the removal of inhibitory phosphates from additional cyclin B-CDK1 molecules and amplifying MPF activity exponentially.^[35] This feedback mechanism ensures rapid and irreversible commitment to mitosis once initiated. Spatial regulation further refines MPF activation by controlling the subcellular localization of cyclin B-CDK1. During G2 phase, cyclin B contains a nuclear export signal (NES) that promotes its cytoplasmic retention, preventing untimely nuclear access and maintaining low nuclear MPF activity; at the onset of G2/M, phosphorylation of the NES by CDK1 masks it, facilitating nuclear import of the complex and enabling targeted activation within the nucleus.^[36] The overall process operates via a threshold model, where MPF activity remains low until cyclin B levels or initial activation signals surpass a critical threshold, after which the positive feedback drives an abrupt, all-or-nothing surge in activity to ensure synchronized mitotic entry across the cell.^[35] This bistable switch-like behavior, modeled mathematically in early studies, integrates multiple inputs to safeguard against partial or erroneous activation.^[34]

Inactivation Mechanisms

The inactivation of maturation promoting factor (MPF), composed of cyclin B and cyclin-dependent kinase 1 (CDK1), is essential for mitotic exit and preventing premature re-entry into the cell cycle. The primary mechanism involves ubiquitin-mediated proteasomal degradation of cyclin B, orchestrated by the anaphase-promoting complex/cyclosome (APC/C), a multi-subunit E3 ubiquitin ligase.^[37] This process targets the N-terminal destruction box motif in cyclin B, marking it for polyubiquitination and subsequent rapid breakdown by the 26S proteasome, which dissociates cyclin B from CDK1 and thereby abolishes MPF activity.^[37] The APC/C remains inactive during early mitosis to allow progression but is activated precisely at the metaphase-anaphase transition to initiate this degradation. Activation of the APC/C for cyclin B degradation requires its co-activator Cdc20, which binds directly to the APC/C and enhances its ubiquitin ligase activity toward cyclin B and other substrates.^[38] Cdc20 recruitment is tightly regulated by the spindle assembly checkpoint (SAC), a surveillance mechanism that inhibits APC/C^Cdc20 until all chromosomes achieve proper bipolar attachment to the mitotic spindle. Upon SAC satisfaction, unattached kinetochores cease generating inhibitory signals (involving Mad1, Mad2, and BubR1 proteins that sequester Cdc20 into the mitotic checkpoint complex), allowing free Cdc20 to activate the APC/C and trigger cyclin B ubiquitination after metaphase alignment. This ensures timely anaphase onset and mitotic progression without errors in chromosome segregation. Following cyclin B degradation, a secondary inhibitory mechanism reinforces MPF inactivation through re-phosphorylation of CDK1 on inhibitory sites Thr14 and Tyr15. This phosphorylation is mediated by the kinases Myt1 (which targets both residues) and Wee1 (primarily Tyr15), whose activities increase as CDK1 levels drop and counterbalance the phosphatase Cdc25 during the M-to-G1 transition.^[39] Such post-degradation phosphorylation prevents residual CDK1 activity from reactivating prematurely, stabilizing the G1 state and contributing to irreversible mitotic exit in systems like Xenopus egg extracts.^[39] Inhibition of Wee1/Myt1 allows rapid re-entry into mitosis even after prolonged G1 arrest, underscoring their role in maintaining low CDK1 activity.^[39] The oscillatory nature of MPF activity is restored in the subsequent cell cycle through de novo synthesis of cyclin B during G2 phase, which binds free CDK1 to reform MPF and initiate the next round of activation. This resynthesis, coupled with initial inhibitory phosphorylations on CDK1, sets up the periodic peaks and troughs of MPF characteristic of cell cycle progression in early embryonic divisions.

Role in the Cell Cycle

Entry into Mitosis

The entry into mitosis, or the G2/M transition, is primarily triggered by the accumulation of active maturation promoting factor (MPF), a complex of cyclin B and cyclin-dependent kinase 1 (CDK1), reaching a critical threshold that drives the cell into prophase.^[1] This threshold ensures that once surpassed, MPF rapidly phosphorylates numerous substrates—estimated at over 100 proteins involved in mitotic restructuring—initiating key events such as nuclear envelope breakdown and chromosome condensation precursors.^[40] The process is facilitated by positive feedback loops where active MPF further activates itself by promoting the dephosphorylation of inhibitory sites on CDK1 via Cdc25 phosphatases, amplifying the signal for irreversible commitment to mitosis.^[34] To safeguard genomic integrity, the G2/M transition integrates checkpoints that delay MPF activation in response to DNA damage or incomplete replication. Specifically, ATM and ATR kinases detect such stresses and phosphorylate downstream effectors like Chk1 and Chk2, which in turn inhibit Cdc25 phosphatases by promoting their sequestration or degradation, thereby preventing the removal of inhibitory phosphates from CDK1 and blocking MPF maturation.^[41] This mechanism ensures that cells do not proceed to mitosis with unrepaired DNA, with experimental evidence from mammalian cells showing that overriding Cdc25 inhibition leads to checkpoint failure and premature mitotic entry.^[42] In mammalian oocytes, MPF plays a specialized role in regulating meiotic arrest, particularly through interactions with the Mos kinase pathway. Fully grown oocytes are held in prophase I arrest until hormonal signals trigger MPF activation for meiotic resumption, but post-ovulation, MPF activity is modulated by Mos, which activates MAPK to stabilize cyclin B levels and maintain metaphase II arrest until fertilization.^[43] This pathway highlights species-specific adaptations, as Mos knockout in mice results in spontaneous meiotic resumption and loss of arrest, underscoring MPF's integration with upstream regulators for oocyte competence.^[44] Quantitatively, MPF activation is modeled as a bistable switch, where the system exhibits two stable states—low (interphase) and high (mitotic) activity—separated by an unstable threshold, ensuring a sharp, all-or-nothing transition.^[45] Pioneering computational models by Tyson and colleagues demonstrate that mutual activation (via Cdc25) and inhibition (via Wee1) loops create hysteresis, making the G2/M commitment irreversible even if cyclin B levels slightly decline, as validated in Xenopus egg extracts and fission yeast.^[46] This framework explains the rapid onset of mitosis observed experimentally, with switch-like behavior confirmed across eukaryotic systems.^[47]

Progression Through Mitotic Phases

During prometaphase, maturation promoting factor (MPF), the cyclin B1-CDK1 complex, maintains high kinase activity to facilitate the formation and stabilization of kinetochore-microtubule attachments. This sustained activity is essential as chromosomes initially attach laterally or via error-prone end-on connections to the assembling mitotic spindle; MPF phosphorylates kinetochore-associated proteins such as CLASP2, in coordination with Polo-like kinase 1 (Plk1), to create a phospho-switch that promotes the transition to stable end-on attachments. Additionally, cyclin B1 localizes to unattached kinetochores, where it contributes to efficient microtubule capture and attachment by locally enhancing CDK1 activity, thereby correcting initial errors and ensuring bipolar orientation.^[48]^[49] In metaphase, MPF's plateaued activity supports chromosome congression to the spindle equator by phosphorylating motor proteins and regulators that balance pulling and ejection forces. For instance, MPF phosphorylates the kinesin-like protein CENP-E at its C-terminal tail, relieving auto-inhibition and restoring its plus-end-directed motility to transport chromosomes toward the equator while counteracting poleward forces from dynein and polar ejection forces along chromosome arms generated by chromokinesins. This phosphorylation-mediated regulation ensures oscillatory movements that refine alignment, with MPF also targeting microtubule-associated proteins to modulate spindle dynamics and maintain tension across sister kinetochores.^[50]^[51] The spindle assembly checkpoint (SAC) indirectly regulates MPF activity through Mad2, which, upon unresolved kinetochore-microtubule attachments, forms a mitotic checkpoint complex that inhibits the anaphase-promoting complex/cyclosome (APC/C), thereby preventing cyclin B1 ubiquitination and sustaining high MPF levels to delay anaphase onset. This checkpoint override mechanism ensures progression only after bi-orientation is achieved, as persistent Mad2 signaling at unattached kinetochores blocks MPF inactivation. MPF's temporal profile during these phases features a sharp increase through prophase, peaking in prometaphase due to positive feedback loops involving Cdc25 phosphatases, followed by a plateau through metaphase until SAC satisfaction triggers APC/C activation.^[52]^[53]

Exit from Mitosis

The exit from mitosis is critically dependent on the inactivation of maturation promoting factor (MPF), a cyclin B-CDK1 complex, which triggers a cascade of events leading to chromosome decondensation, nuclear envelope reformation, and cell division completion. At the onset of anaphase, partial inactivation of MPF removes its inhibitory phosphorylation on separase, thereby allowing separase activation and subsequent cleavage of cohesin subunits that hold sister chromatids together. This process ensures the physical separation of chromosomes, marking the transition from metaphase to anaphase.^[54] During telophase, the full reversal of mitotic phosphorylation states is mediated by protein phosphatase 2A (PP2A), particularly the B55 regulatory subunit variant (PP2A-B55), which dephosphorylates numerous MPF-phosphorylated substrates to restore the interphase cellular architecture. Activated upon MPF decline, PP2A-B55 targets over 2,900 phosphosites, including those on proteins involved in spindle disassembly and nuclear envelope reassembly, such as NUP153 and PRC1, with kinetics determined by substrate-specific motifs that prioritize rapid dephosphorylation of key regulators. This coordinated dephosphorylation prevents premature interphase progression and ensures orderly mitotic exit. The anaphase-promoting complex/cyclosome (APC/C) contributes to MPF inactivation through cyclin B ubiquitination and degradation. The decline in MPF activity also coordinates cytokinesis by enabling the assembly of the central spindle and contractile ring ingression. High MPF levels during metaphase phosphorylate components of the central spindle machinery, such as PRC1 and ECT2, inhibiting their localization and function; upon MPF inactivation via cyclin B degradation, dephosphorylation of these targets allows bundling of antiparallel microtubules at the spindle midzone and recruitment of RhoA-GEFs to drive actin-myosin contractility for furrow formation and progression. This temporal control ensures cytokinesis initiates only after chromosome segregation, avoiding errors in daughter cell partitioning. Finally, the low MPF levels post-mitosis provide negative feedback to establish the G1 phase by permitting dephosphorylation of the retinoblastoma protein (Rb), which in its hypophosphorylated form binds and represses E2F transcription factors to silence genes required for S-phase entry. Rb remains hyperphosphorylated from earlier cell cycle phases during mitosis; the subsequent drop in CDK1 activity allows phosphatases like PP1 to reverse this, reactivating Rb to maintain E2F repression and enforce a G1 checkpoint until mitogenic signals reinitiate the cycle. This mechanism links mitotic completion to restriction point control, preventing unscheduled proliferation.^[16]

Physiological Functions and Targets

Nuclear Envelope Breakdown

Maturation promoting factor (MPF), a complex of cyclin B and cyclin-dependent kinase 1 (CDK1), plays a central role in initiating nuclear envelope breakdown (NEBD) at the onset of prophase by directly phosphorylating components of the nuclear lamina.^[55] This process disassembles the nuclear barrier, enabling the mitotic spindle to access chromosomes during cell division.^[56] The primary targets of MPF are the B-type lamins, particularly lamin B1 and B2, which form the structural meshwork of the nuclear lamina. MPF phosphorylates lamin B1 at serine 23 in the N-terminal head domain and serine 393 in the C-terminal tail domain, with sites on lamin B2 including serine 17 (N-terminal), threonine 34, serine 37, and serine 405.^[57] These phosphorylation events, occurring rapidly upon MPF activation, lead to depolymerization of lamin filaments. The mechanism involves disruption of head-to-tail polymer interactions within the lamin coiled-coil domains, which destabilizes the filamentous network and solubilizes the lamina into non-sedimentable forms.^[56]^[58] The disassembly of the nuclear lamina has critical consequences for mitotic progression, as it fragments the nuclear envelope into vesicles and allows microtubules from the forming spindle to interact directly with chromosomes.^[55] This facilitates proper chromosome alignment and segregation. In telophase, NEBD is reversed through dephosphorylation of these sites by protein phosphatases such as PP1 and PP2A, which restores lamin polymerization and promotes nuclear envelope reassembly around daughter nuclei.^[59]^[60] Experimental evidence for MPF's role in NEBD comes from microinjection studies in Xenopus laevis embryos. Injection of purified MPF into cycloheximide-arrested interphase embryos, which contain multiple nuclei in a shared cytoplasm, induces rapid nuclear envelope dispersal within 5 minutes, as visualized by immunofluorescence staining of the nuclear lamina.^[61] This breakdown occurs at MPF concentrations similar to those active during oocyte maturation, confirming MPF's sufficiency to trigger lamina disassembly independently of other cell cycle events.^[61]

Chromosome Condensation

Maturation promoting factor (MPF), the cyclin B-CDK1 complex, plays a central role in initiating chromosome condensation during the entry into mitosis by phosphorylating key substrates that drive chromatin compaction. Among its primary targets are the structural maintenance of chromosomes (SMC) subunits SMC2 and SMC4 of the condensin complexes, which form the core of condensin I and II. Phosphorylation of these subunits by MPF enhances the DNA-binding affinity and ATPase activity of condensins, enabling them to organize chromatin into higher-order looped structures that facilitate axial shortening and compaction of chromosomes.^[62]^[63] In parallel, phosphorylation of histone H3 at serine 10 (Ser10), primarily by Aurora B kinase upon MPF activation, correlates closely with mitotic chromosome condensation and supports the structural changes necessary for proper packing. This phosphorylation aids in the dissociation of heterochromatin proteins and promotes the compaction of nucleosomes, working in concert with condensin-mediated looping to achieve the rod-like morphology of mitotic chromosomes. The mechanism involves condensin activation, where phosphorylated SMC2/SMC4 subunits loop DNA segments into stable scaffolds, while H3 Ser10 phosphorylation further stabilizes these interactions by altering chromatin accessibility and rigidity.^[64]^[65] Chromosome condensation begins in prophase upon MPF activation and progresses to completion by prometaphase, coinciding with nuclear envelope breakdown. This timing ensures that chromosomes are sufficiently compacted for alignment on the metaphase plate. The process requires synergy with Aurora B kinase, which reinforces H3 Ser10 phosphorylation and condensin recruitment, amplifying MPF's effects to achieve full condensation.^[66]^[67] Defects in MPF-mediated phosphorylation, such as hypo-phosphorylation of condensins or histone H3 Ser10, disrupt proper compaction and lead to the formation of anaphase bridges, where under-condensed chromatin trails between segregating daughter cells, resulting in genomic instability and segregation errors.^[68]^[65]

Spindle Assembly and Cytokinesis

Maturation promoting factor (MPF), consisting of cyclin B1-bound Cdk1, plays a pivotal role in orchestrating spindle assembly by phosphorylating key regulators of microtubule nucleation at kinetochores. Specifically, MPF phosphorylates targeting protein for Xklp2 (TPX2) at threonine 72, which enhances TPX2's ability to activate Aurora A kinase and promote microtubule nucleation and stabilization around chromosomes, facilitating the formation of a robust bipolar spindle.^[69] Through these and other phosphorylations, MPF modulates microtubule dynamics to stabilize the bipolar spindle. By phosphorylating stathmin/OP18, MPF inhibits its catastrophe-promoting activity, thereby suppressing microtubule depolymerization events and favoring the persistence of spindle microtubules essential for kinetochore capture and alignment.^[70] This stabilization is critical during metaphase, where sustained MPF activity maintains spindle integrity against dynamic instabilities. As MPF activity declines toward anaphase, dephosphorylation events allow astral microtubules to elongate, enabling spindle repositioning and orientation within the cell cortex to specify the division plane. In cytokinesis, MPF coordinates the activation of the contractile ring via the ECT2/RhoA pathway. During early mitosis, MPF phosphorylates the Rho guanine nucleotide exchange factor ECT2, initially sequestering it to prevent premature RhoA activation and contractile ring formation.^[71] The subsequent decline in MPF activity at anaphase onset releases this inhibition, allowing ECT2 to localize to the central spindle, activate RhoA, and drive myosin II recruitment for equatorial furrow ingression and contractile ring assembly.^[72] The spindle assembly checkpoint (SAC) further integrates MPF regulation, where unattached kinetochores generate a feedback signal via Aurora B kinase to sustain MPF levels. Aurora B, activated at error-prone attachments, phosphorylates kinetochore substrates to destabilize incorrect microtubule bindings, thereby maintaining SAC signaling that inhibits the anaphase-promoting complex/cyclosome (APC/C) and prevents cyclin B1 degradation, ensuring MPF persistence until all kinetochores achieve stable bipolar attachments.^[73]

Clinical and Research Implications

Dysregulation in Cancer

Dysregulation of maturation promoting factor (MPF), composed of cyclin B1 and CDK1, plays a significant role in tumorigenesis by disrupting normal cell cycle control. Overexpression of cyclin B1, a key component of MPF, occurs in approximately 50% of solid tumors, with median prevalence rates around 48.78% across various studies. This upregulation is particularly noted in breast cancer (about 42% of cases) and non-small cell lung cancer (up to 58% in some cohorts), where it correlates with aggressive disease and poor prognosis, including reduced 3-year overall survival (odds ratio [OR] = 2.05, 95% CI = 1.20–3.50) and 5-year overall survival (OR = 2.11, 95% CI = 1.33–3.36).^[74] In breast cancer, high cyclin B1 levels are an independent prognostic factor associated with tumor aggressiveness.^[75] Similarly, in lung cancer, cyclin B1 overexpression predicts worse survival outcomes (3-year OS OR = 2.95, 95% CI = 1.60–5.44; 5-year OS OR = 2.60, 95% CI = 1.46–4.63).^[74] Mutations and pathway alterations leading to CDK1 hyperactivation further contribute to cancer progression and therapy resistance. Loss of p53 function, common in over 50% of human cancers, impairs the G1/S checkpoint, causing cells to depend heavily on the G2/M checkpoint regulated by Wee1-mediated inhibitory phosphorylation of CDK1.^[76] This reliance promotes chemoresistance, as p53-deficient tumors evade DNA damage-induced arrest. Inhibition of Wee1 removes this brake, resulting in CDK1 hyperactivation and premature mitotic entry, which selectively sensitizes p53-mutant cells to chemotherapy by inducing mitotic catastrophe.^[77] For instance, Wee1 inhibitors overcome cisplatin resistance in high-risk neuroblastoma models with p53 pathway defects.^[78] Therapeutic strategies targeting MPF dysregulation have shown promise in preclinical models. Selective CDK1 inhibitors, such as RO-3306, an ATP-competitive agent, exhibit potent anti-tumor activity by inducing G2/M arrest and apoptosis in various cancers, including osteosarcoma and neuroblastoma.^[79]^[80] RO-3306 has demonstrated efficacy in patient-derived xenograft models when combined with sorafenib, reducing tumor growth through blockade of CDK1/PDK1/β-catenin signaling.^[81] Additionally, combining CDK1 inhibition with modulation of the anaphase-promoting complex/cyclosome (APC/C), which degrades cyclin B to inactivate MPF, enhances therapeutic outcomes; APC/C activators like CDH1 promote cyclin B destruction, synergizing with CDK1 inhibitors to enforce cell cycle exit in tumor cells.^[82]^[83] Recent research up to 2025 highlights MPF as a synthetic lethal target in p53-mutant cancers via CRISPR screens. Genome-wide CRISPR/Cas9 screens have identified vulnerabilities in the MPF pathway, where loss of p53 sensitizes cells to perturbations in CDK1 or cyclin B1, leading to selective lethality. For example, dual inhibitors targeting cyclin A/B interactions (key for MPF activation) selectively kill small cell lung cancer cells with high E2F activity and G1/S checkpoint defects, common in p53-mutant tumors.^[84] These findings underscore MPF's role in post-2000 studies of tumorigenesis and support its exploitation for precision therapies in p53-deficient malignancies.^[85]

Therapeutic Targeting

Direct inhibitors of maturation promoting factor (MPF), primarily targeting the CDK1 subunit, have been developed to disrupt uncontrolled cell proliferation in malignancies. Dinaciclib, an ATP-competitive inhibitor with activity against CDK1, CDK2, CDK5, and CDK9, has demonstrated encouraging single-agent activity in chronic lymphocytic leukemia (CLL), a form of leukemia, in Phase II clinical trials conducted in the 2010s and reported through the 2020s. In these trials, dinaciclib achieved an objective response rate of approximately 58% in relapsed or refractory CLL patients, with manageable toxicity profiles including cytopenias.^[86] Purvalanol A, another ATP-competitive CDK1 blocker, has shown preclinical efficacy in pediatric acute myeloid leukemia (AML) models, particularly when combined with anti-apoptotic agents like ABT-737 to enhance cell death in leukemic blasts.^[87] Indirect modulation of MPF activity through upstream regulators represents another therapeutic avenue, especially in hematologic cancers. Polo-like kinase 1 (PLK1) inhibitors, such as volasertib, interfere with the positive feedback loop that activates MPF by phosphorylating CDC25 phosphatases and inhibiting WEE1 kinase. Volasertib received orphan drug designation in the European Union and United States for AML treatment and was evaluated in a Phase III trial for patients ineligible for standard induction chemotherapy, where it improved overall survival when added to low-dose cytarabine compared to cytarabine alone, though the trial did not meet its primary endpoint due to toxicity concerns like neutropenia.^[88]^[89] Emerging approaches leverage proteolysis-targeting chimeras (PROTACs) to induce ubiquitin-mediated degradation of CDK1 or cyclin B, bypassing the limitations of reversible inhibition. PROTACs such as those based on CDK1 ligands conjugated to E3 ligase recruiters (e.g., cereblon binders) have effectively degraded CDK1 in breast cancer cell lines, leading to G2/M arrest and reduced proliferation without affecting non-dividing cells. These degraders offer enhanced selectivity and duration of action compared to small-molecule inhibitors.^[90] In reproductive contexts, nanoparticle-based delivery systems, including gold nanoparticles, have been employed to augment oocyte maturation and embryonic development in infertility models by stabilizing MPF activity post-activation, improving blastocyst formation rates in artificially activated mouse oocytes.^[91]^[92] Key challenges in MPF-targeted therapies include achieving isoform-specific inhibition of CDK1 amid high structural homology with other CDKs in the ATP-binding pocket, which often results in off-target effects and dose-limiting toxicities like gastrointestinal issues and myelosuppression. Ongoing research addresses this through allosteric inhibitors and cyclin-specific degraders to minimize pan-CDK activity. As of November 2025, no selective CDK1 inhibitors have been approved for clinical use, with efforts focusing on combination therapies to improve efficacy and safety. Additionally, investigations into MPF dysregulation in non-oncologic conditions, such as CDK1-mediated tau hyperphosphorylation contributing to neurodegeneration in Alzheimer's disease, highlight potential broader applications, though clinical translation remains exploratory.^[91]^[93]

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