Biomedical subjects

Hiroshi Nojima

Publications and source records attributed to Hiroshi Nojima.

At least 19 recordsLinked to original sources

PubMed2006

A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization.

Damage to the mitotic spindle and centrosome dysfunction can lead to cancer. To prevent this, cells trigger a succession of checkpoint responses, where an initial mitotic delay is followed by slippage without cytokinesis, spawning tetraploid G1 cells that undergo a p53-dependent G1/S arrest. We describe the importance of Lats2 (Large Tumor Suppressor 2) in this checkpoint response. Lats2 binds Mdm2, inhibits its E3 ligase activity, and activates p53. Nocodazole, a microtubule poison that provokes centrosome/mitotic apparatus dysfunction, induces Lats2 translocation from centrosomes to the nucleus and p53 accumulation. In turn, p53 rapidly and selectively up-regulates Lats2 expression in G2/M cells, thereby defining a positive feedback loop. Abrogation of Lats2 promotes accumulation of polyploid cells upon exposure to nocodazole, which can be prevented by direct activation of p53. The Lats2-Mdm2-p53 axis thus constitutes a novel checkpoint pathway critical for the maintenance of proper chromosome number.

Animals↗

PubMed2006

Isolation and characterization of the TIGA genes, whose transcripts are induced by growth arrest.

We report here the isolation of 44 genes that are upregulated after serum starvation and/or contact inhibition. These genes have been termed TIGA, after Transcript Induced by Growth Arrest. We found that there are two kinds of G0 phases caused by serum starvation, namely, the shallow G0 (or G0/G1) and the deep G0 phases. The shallow G0 is induced by only a few hours of serum starvation, while deep G0 is generated after 3 days of serum starvation. We propose that mammalian cells enter deep G0 through a G0 gate, which is only opened on the third day of serum starvation. TIGA1, one of the uncharacterized TIGA genes, encodes a homolog of cyanate permease of bacteria and localizes in mitochondria. This suggests that Tiga1 is involved in the inorganic ion transport and metabolism needed to maintain the deep G0 phase. Ectopic expression of TIGA1 inhibited not only tumor cell proliferation but also anchorage-independent growth of cancer cell lines. A microsatellite marker, ENDL-1, allowed us to detect loss of heterozygosity around the TIGA1 gene region (5q21-22). Further analysis of the TIGA genes we have identified here may help us to better understand the mechanisms that regulate the G0 phase.

Amino Acid Sequence↗

PubMed2006

Specific down-regulation of spinal mu-opioid receptor and reduced analgesic effects of morphine in mice with postherpetic pain.

The analgesic effects of opioid agonists and the expression of mu- and kappa-opioid receptors were compared between mice with herpetic pain and those with postherpetic pain induced by herpetic virus inoculation. Morphine inhibited herpetic pain more effectively than postherpetic pain. Intrathecal injection reduced the analgesic effects of morphine on postherpetic pain, but intracerebroventricular injection did not. The kappa-opioid receptor agonist nalfurafine suppressed herpetic and postherpetic pain to similar degrees. mu-Opioid receptor-like immunoreactivities in the lumbar dorsal horn were markedly decreased at the postherpetic, but not herpetic, stage of pain. In the dorsal root ganglia, the expression of mu-opioid receptor mRNA was significantly decreased in mice with postherpetic pain, whereas the kappa-opioid receptor mRNA level was not altered. These results suggest that specific down-regulation of the mu-opioid receptor in the primary sensory neurons is responsible for the reduced analgesic action of morphine on postherpetic pain. The kappa-opioid receptor may be a useful target for the analgesic treatment of postherpetic neuralgia.

Analgesics, Opioid↗

PubMed2006

Isolation and expression profiling of genes upregulated in bone marrow-derived mononuclear cells of rheumatoid arthritis patients.

We have comprehensively identified the genes whose expressions are augmented in bone marrow-derived mononuclear cells (BMMC) from patients with Rheumatoid Arthritis (RA) as compared with BMMCs from Osteoarthritis (OA) patients, and named them AURA after augmented in RA. Both stepwise subtractive hybridization and microarray analyses were used to identify AURA genes, which were confirmed by northern blot analysis and/or reverse transcription polymerase chain reaction (RT-PCR). We also assessed their expression levels in individual patients by quantitative real-time RT-PCR. Of 103 AURA genes we have identified, the mRNA levels of the following 10 genes, which are somehow related to immune responses, were increased in many of the RA patients: AREG (=AURA9), FK506-binding protein 5 (FKBP5 = AURA45), C-type lectin superfamily member 9 (CLECSF9 = AURA24), tyrosylprotein sulfotransferase 1 (TPST1 = AURA52), lymphocyte G0/G1 switch gene (G0S2 = AURA8), chemokine receptor 4 (CXCR4 = AURA86), nuclear factor-kappa B (NF-kappaB = AURA25) and two genes of unknown function (FLJ11106 = AURA1, BC022398 = AURA2 and XM_058513 = AURA17). Since AREG was most significantly increased in many of the RA patients, we subjected it to further analysis and found that AREG-epidermal growth factor receptor signaling is highly activated in synovial cells isolated from RA patients, but not in OA synoviocytes. We propose that the expression profiling of these AURA genes may improve our understanding of the pathogenesis of RA.

Amphiregulin↗

PubMed2006

The cannabinoid CB2 receptor inverse agonist JTE-907 suppresses spontaneous itch-associated responses of NC mice, a model of atopic dermatitis.

JTE-907, N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide, is a selective cannabinoid CB2 receptor antagonist/inverse agonist. The anti-pruritic activity of JTE-907 was studied in NC mice with chronic dermatitis, a model of atopic dermatitis. The oral dose of JTE-907 (1 and 10 mg/kg/day), an immunosuppressant agent tacrolimus (1 mg/kg/day) and a glucocorticoid betamethasone 17-valerate (1 mg/kg/day) for 20 days suppressed the spontaneous scratching and cutaneous nerve activity of NC mice. JTE-907 (10, but not 1, mg/kg) and tacrolimus, but not betamethasone, tended to alleviate the dermatitis. Betamethasone inhibited the body weight gain. These results suggest that JTE-907 suppresses spontaneous itch-associated responses of NC mice without adverse effects such as weight loss.

Administration, Oral↗

PubMed2006

Transcription factors, cAMP-responsive element modulator (CREM) and Tisp40, act in concert in postmeiotic transcriptional regulation.

We previously isolated 80 TISP (transcript induced in spermiogenesis) genes whose transcription is dramatically induced during spermiogenesis. Our analysis here of the expression of these genes in the testis of the cAMP-responsive element modulator (CREM)-null mouse revealed that 54 TISP genes are under the transcriptional regulation of CREM. One CREM-regulated gene is TISP40, which encodes a basic leucine zipper (bZip)-type transcription factor bearing a transmembrane domain that generates the two proteins Tisp40alpha and Tisp40beta. Both of these proteins function by binding to UPRE (unfolded protein-response element) but do not recognize CRE motifs. We show here that Tisp40alpha mRNA is generated under the direct transcriptional regulation of CREM. CREMtau and Tisp40 form a heterodimer, which functions through CRE but not through UPRE. Furthermore, binding ability of CREM to CRE is dramatically up-regulated by forming a heterodimer with Tisp40alphaDeltaTM, a truncated form of Tisp40alpha that lacks the transmembrane domain. We confirmed that Tisp40 and CREM actually bind to the Tisp40 promoter in vivo by chromatin immunoprecipitation assay. Finally, we demonstrate that the Tisp40DeltaTM-CREMtau heterodimer acts as a recruiter of HIRA, a histone chaperone, to CRE. Taken together, we propose that Tisp40 is an important transcriptional regulator during spermiogenesis.

Animals↗

PubMed2006

Mcp5, a meiotic cell cortex protein, is required for nuclear movement mediated by dynein and microtubules in fission yeast.

During meiotic prophase I of the fission yeast Schizosaccharomyces pombe, oscillatory nuclear movement occurs. This promotes homologous chromosome pairing and recombination and involves cortical dynein, which plays a pivotal role by generating a pulling force with the help of an unknown dynein anchor. We show that Mcp5, the homologue of the budding yeast dynein anchor Num1, may be this putative dynein anchor. mcp5+ is predominantly expressed during meiotic prophase, and GFP-Mcp5 localizes at the cell cortex. Moreover, the mcp5Delta strain lacks the oscillatory nuclear movement. Accordingly, homologous pairing and recombination rates of the mcp5Delta strain are significantly reduced. Furthermore, the cortical localization of dynein heavy chain 1 appears to be reduced in mcp5Delta cells. Finally, the full function of Mcp5 requires its coiled-coil and pleckstrin homology (PH) domains. Our results suggest that Mcp5 localizes at the cell cortex through its PH domain and functions as a dynein anchor, thereby facilitating nuclear oscillation.

Biological Clocks↗

PubMed2006

A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors.

Endogenous small RNAs (miRNAs) regulate gene expression by mechanisms conserved across metazoans. While the number of verified human miRNAs is still expanding, only few have been functionally annotated. To perform genetic screens for novel functions of miRNAs, we developed a library of vectors expressing the majority of cloned human miRNAs and created corresponding DNA barcode arrays. In a screen for miRNAs that cooperate with oncogenes in cellular transformation, we identified miR-372 and miR-373, each permitting proliferation and tumorigenesis of primary human cells that harbor both oncogenic RAS and active wild-type p53. These miRNAs neutralize p53-mediated CDK inhibition, possibly through direct inhibition of the expression of the tumor-suppressor LATS2. We provide evidence that these miRNAs are potential novel oncogenes participating in the development of human testicular germ cell tumors by numbing the p53 pathway, thus allowing tumorigenic growth in the presence of wild-type p53.

Cells, Cultured↗

PubMed2006

Isolation and expression profiling of genes upregulated in the peripheral blood cells of systemic lupus erythematosus patients.

We have identified the genes whose expressions are augmented in the blood cells of the patients with systemic lupus erythematosus (SLE) using the 'stepwise subtraction' technique along with microarray analysis. The expression levels of these genes were assessed by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) in 31 SLE patients and 30 healthy controls. We found that the transcription levels of following eight genes were significantly increased in SLE patients; interferon (IFN)-alpha-inducible protein 27 (IFI27), IFN-alpha-inducible protein IFI-15K (G1P2), IFN stimulated gene 20 kDa (ISG20), epithelial stromal interaction 1 (EPSTI1), defensin-alpha (DEFA3), amphiregulin (AREG) and two genes of unknown function (BLAST accession nos AL050290 and AY358224 = SLED1). In comparison with idiopathic thrombocytopenic purpura (ITP), an organ-specific autoimmune disease, IFI27, G1P2 and SLED1 were preferentially upregulated in SLE. In contrast, AREG and AL050290 were more highly expressed in ITP than in SLE. We correlated changes in gene expression and clinical/laboratory features of SLE and found that expression of ISG20, EPSTI1 and SLED1 are significantly correlated with lymphocyte counts. Genes linked to IFN are well known to influence SLE, but several other novel genes unrelated to IFN signaling we report here would be useful to understand the pathophysiology of SLE.

Female↗

PubMed2006

Glycycoumarin from Glycyrrhizae Radix acts as a potent antispasmodic through inhibition of phosphodiesterase 3.

Glycyrrhizae Radix is used to treat abdominal pain as a component of Shakuyaku-kanzo-to, a traditional Chinese medicine formulation. We aim at clarifying the antispasmodic principles of Glycyrrhizae Radix, and consequently isolated glycycoumarin as a potent relaxant on the carbamylcholine (CCh)-induced contraction of mouse jejunum. In this paper we investigated the effects and the action mechanism of glycycoumarin on the contraction of mouse jejunum. Glycycoumarin inhibited the contraction induced by various types of stimulants, such as CCh, KCl, BaCl(2), and A23187 (calcium ionophore III) with IC(50) values of 2.93+/-0.94 micromol/l (1.08+/-0.35 microg/ml), 2.59+/-0.58 micromol/l (0.95+/-0.29 microg/ml), 4.09+/-1.82 micromol/l (1.51+/-0.67 microg/ml) and 7.39+/-5.19 micromol/l (2.72+/-1.91 microg/ml), respectively, with a potency similar to that of papaverine (a representative antispasmodic for smooth muscle). Furthermore, pretreatment with glycycoumarin enhanced the relaxation induced by forskolin on CCh-evoked contraction, similar to that by pretreatment with IBMX, a non-specific inhibitor of phosphodiesterases (PDEs). Pretreatment with glycycoumarin also enhanced the relaxation effect of rolipram, a specific inhibitor of PDE isozyme 4, as pretreatment with milrinone, a specific inhibitor of isozyme 3, did. Moreover, the effect of glycycoumarin was associated with dose-dependent accumulation of cAMP, but not cGMP, in mouse jejunum. These results indicate that glycycoumarin has an inhibitory effect on smooth muscle contraction induced by various types of stimulants through the inhibition of PDEs, especially isozyme 3, followed by the accumulation of intracellular cAMP.

Animals↗

PubMed2006

Major histocompatibility complex haplotype is associated with postherpetic pain in mice.

BACKGROUND: Postherpetic neuralgia is one of the major complications of herpes zoster caused by the reactivation of varicella-zoster virus and is characterized by severe pain. The authors previously showed the association of a human major histocompatibility complex (MHC) haplotype with postherpetic neuralgia. This study was performed to experimentally confirm the role of MHC haplotype in the development of postherpetic pain using a mouse model of postherpetic pain, which corresponds to postherpetic neuralgia. METHODS: BALB/c mice (MHC haplotype: H-2), C57BL/6 mice (MHC haplotype: H-2), and BALB/b mice, a congenic BALB/c strain with H-2, were used. Herpes simplex virus type I was transdermally inoculated on the hind paw. Unilaterally zosteriform skin lesion and pain-related responses (acute herpetic pain) were caused, and some mice showed pain-related responses (postherpetic pain) after the cure of skin lesions. Herpes simplex virus type I antigen and CD3-positive cells were immunostained in the dorsal root ganglion in the acute phase. RESULTS: The incidence (78%) of postherpetic pain in C57BL/6 mice was significantly higher than that (35%) in BALB/c mice (P = 0.004, odds ratio = 6.7). Furthermore, the incidence of postherpetic pain in BALB/b (H-2) was similar to that in C57BL/6. Herpes simplex virus type I antigen-positive cells were less in the dorsal root ganglion of C57BL/6 mice than that of BALB/c mice. CD3-positive T cells were more in the dorsal root ganglion of C57BL/6 mice than BALB/c mice. CONCLUSIONS: These results suggest that the MHC haplotype (H-2) is involved in the incidence of postherpetic pain, and CD3-positive T cells may play a role in its pathogenesis.

Animals↗

PubMed2006

The testes-specific bZip type transcription factor Tisp40 plays a role in ER stress responses and chromatin packaging during spermiogenesis.

We previously reported that the spermatid-specific transcription factor Tisp40 functions through UPRE and CRE. To investigate Tisp40 function in vivo, we generated TISP40(-/-) mice. TISP40(-/-) mice were born at expected ratios, were healthy, and mutant males bred normally. However, the ER stress-response protein Grp78/BiP accumulated in the TISP40(-/-) testis and RAMP4 (Ribosome-associated membrane protein 4) mRNA level was up-regulated. Disruption of TISP40 caused ER stress and activation of caspase 12 but not caspase 9, leading to apoptosis of meiotic/postmeiotic germ cells. On the other hand, DAPI staining and electron microscopy revealed that epididymal sperm nuclei were abnormally relaxed in the TISP40(-/-) testis, a phenotype that was independent of the expression and maturation of transition proteins and protamines but due to abnormally retained histones. Histones localized to the cytoplasm as well as to the nucleus and were also retained in epididymal sperm. Histones H2A and H4 were dramatically up-regulated and the acetylation of H2A, H2B and H4 was also enhanced in the TISP40(-/-) testis. Taken together, we conclude that Tisp40 plays an important role in the unfolded protein response of the testis and in regulating the maturation of sperm head nuclei.

Animals↗

PubMed2006

Spo5/Mug12, a putative meiosis-specific RNA-binding protein, is essential for meiotic progression and forms Mei2 dot-like nuclear foci.

We report here a functional analysis of spo5(+)(mug12(+)) of Schizosaccharomyces pombe, which encodes a putative RNA-binding protein. The disruption of spo5(+) caused abnormal sporulation, generating inviable spores due to failed forespore membrane formation and the absence of a spore wall, as determined by electron microscopy. Spo5 regulates the progression of meiosis I because spo5 mutant cells display normal premeiotic DNA synthesis and the timely initiation of meiosis I but they show a delay in the peaking of cells with two nuclei, abnormal tyrosine 15 dephosphorylation of Cdc2, incomplete degradation of Cdc13, retarded formation and repair of double strand breaks, and a reduced frequency of intragenic recombination. Immunostaining showed that Spo5-green fluorescent protein (GFP) appeared in the cytoplasm at the horsetail phase, peaked around the metaphase I to anaphase I transition, and suddenly disappeared after anaphase II. Images of Spo5-GFP in living cells revealed that Spo5 forms a dot in the nucleus at prophase I that colocalized with the Mei2 dot. Unlike the Mei2 dot, however, the Spo5 dot was observed even in sme2Delta cells. Taken together, we conclude that Spo5 is a novel regulator of meiosis I and that it may function in the vicinity of the Mei2 dot.

Amino Acid Sequence↗

PubMed2006

RECS1 is a negative regulator of matrix metalloproteinase-9 production and aged RECS1 knockout mice are prone to aortic dilation.

BACKGROUND: RECS1 is a mechanical stress responsive gene and RECS1 knockout (KO) mice (older than 14 months) are prone to cystic medial degeneration (CMD). The present study was designed to assess whether RECS1 KO mice have altered gelatinase (matrix metalloproteinase (MMP)-2 and MMP-9) levels and whether they are prone to aortic dilation. METHODS AND RESULTS: Aortic and plasma gelatinase levels in RECS1 KO and wild-type (WT) mice were assessed by gelatin zymography and Western blot analysis. Pro-MMP-9 (in the aorta), neutrophil gelatinase-associated lipocalin/MMP-9 complex (NGAL-MMP-9, in plasma), and active-MMP-9 protein levels were more abundant in KO mice throughout adulthood compared with WT mice. Aortic MMP-2, aortic MMP-9, and plasma MMP-9 activation increased with age, even though the aortic pro-MMP-9, plasma NGAL-MMP-9, aortic and plasma pro-MMP-2 production decreased: this was true both for the WT and KO animals. Aortic pro-MMP-2, aortic active-MMP-2, and plasma pro-MMP-2 protein levels were higher in the aged KO mice, but they were lower in the young KO mice than those in WT mice. Thoracic aortic dilation was observed only in the aged KO mice. In situ zymographic experiments confirmed that the increased aortic gelatinase activities were associated with CMD and aortic dilation observed in the aged KO mice. CONCLUSIONS: RECS1 negatively regulates aortic MMP-9 production and knocking out RECS1 induces susceptibility to aortic dilation as well as CMD in the aged mice. The present study suggests that RECS1 plays protective roles in vascular remodeling. We speculate that inhibiting unfavorable deposition and extracellular matrix degradation are both important for prevention and treatment of aneurysms.

Aging↗

PubMed2006

RECS1 deficiency in mice induces susceptibility to cystic medial degeneration.

RECS1 is a novel shear stress-responsive gene that encodes a protein putatively forming seven-span transmembrane domains. We reports here that mouse RECS1 (mRECS1) transcripts is detected in most tissues except for thymus, spleen and testis. The putative cytoplasmic N-terminus of mRECS1 has a high content of proline (23%) and glycine (12%) residues, contains one PPXY motif, multiple PXXP motifs and one overlapping P(T/S)AP and PPXY motif (P(T/S)APPXY). The PPXY motif lies within one potential PEST sequence (PEST score: +7.65). We prepared anti-RECS1 polyclonal antibody and found by western blot analysis that the mRECS1 protein in the lung and aorta was detected as a 34.4 kDa band. However, one shifted 58 kDa band or three shifted bands (48, 69, 82 kDa) were detected in the heart or the liver, respectively. Since northern blot detected only one species of mRECS1 mRNA in heart and liver tissues, as well as other tissues (approximately 2.2 kb), these differences in molecular weight seem to be due to posttranslational modification. Biochemical fractionation and RECS1-GFP fusion protein revealed that RECS1 localizes at the endosomal/lysosomal membranes in the cytoplasm. To understand the function of RECS1 in the body, we made RECS1 knockout (KO) mice and found that RECS1 KO mice (older than 14 months) are prone to cystic medial degeneration (CMD). Taken together, we conclude that RECS1 is an endosomal/lysosomal membrane protein which plays protective roles in vascular remodeling.

Amino Acid Sequence↗

PubMed2005

Potent pruritogenic action of tryptase mediated by PAR-2 receptor and its involvement in anti-pruritic effect of nafamostat mesilate in mice.

The pruritogenic potency of tryptase and its involvement in anti-pruritic effect of intravenous nafamostat mesilate (NFM) were studied in mice. An intradermal injection of tryptase (0.05-1 ng/site) elicited scratching in ICR mice, while chymase was without effects at doses of 0.05-50 ng/site. The dose-response curve of tryptase action was bell-shaped and the effect peaked at 0.1 ng/site (approximately 0.7 fmol/site). NFM (10 mg/kg) inhibited scratching induced by tryptase but not by histamine and serotonin. NFM (1-10 mg/kg) produced the dose-dependent inhibition of scratching induced by intradermal compound 48/80 (10 microg/site). The inhibition by NFM (10 mg/kg) was abolished in mast cell-deficient (WBB6F1 W/W(V)) mice, but not in wild-type (WBB6F1 +/+) mice. NFM (10 mg/kg) suppressed tryptase activity in the mouse skin. Proteinase-activated receptor-2 (PAR-2) neutralizing antibody (0.1 and 1 microg/site) and the PAR-2 antagonist FSLLRY (10 and 100 microg/site) inhibited scratching induced by tryptase (0.1 ng/site) and compound 48/80 (10 microg/site). These results suggest that mast cell tryptase elicits itch through PAR-2 receptor and that NFM inhibits itch-associated responses mainly through the inhibition of mast cell tryptase.

Animals↗

PubMed2005

A B56 regulatory subunit of protein phosphatase 2A localizes to nuclear speckles in cardiomyocytes.

Protein phosphatase 2A (PP2A) is widely distributed in heart tissues, yet its precise cellular functions are poorly understood. This study is based on the notion that PP2A action is governed by interactions of the core enzyme with B targeting/regulatory subunits. The subcellular localizations of two B subunits, B56alpha and B56gamma1, were assessed using adenovirus-driven expression of epitope-tagged (hemagglutinin, HA) in cultured neonatal and adult rat ventricular myocytes. Confocal imaging revealed that HA-B56alpha was excluded from the nucleus and decorated striated structures, whereas HA-B56gamma1 was principally found in the nucleus. Precise immunolabeling studies showed that B56gamma1 was concentrated in intranuclear structures known as nuclear speckles, macromolecular structures that accumulate transcription and splicing factors. Western blot analyses revealed that overexpression of either B subunit had no effect on the levels of other PP2A subunits in cultured neonatal cardiac cells. However, overexpression of only B56gamma1 increased whole cell PP2A activity by 40% when measured in cell extracts. Finally, B56gamma1 did not alter global gene expression or expression of hypertrophic gene markers such as alpha-skeletal actin. However, morphometric analyses of confocal images revealed that B56gamma1 alters the dynamic assembly/disassembly process of nuclear speckles in heart cells. These studies provide new insight into mechanisms of PP2A targeting in the subnuclear architecture in cardiomyocytes and into the role of this phosphatase in nuclear signaling.

Amino Acid Sequence↗

PubMed2005

Cyclin G1 and cyclin G2 are expressed in the periimplantation mouse uterus in a cell-specific and progesterone-dependent manner: evidence for aberrant regulation with Hoxa-10 deficiency.

Because uterine cell-specific proliferation, differentiation, and apoptosis are differentially regulated during the periimplantation period, we speculated that negative cell cycle regulators are also operative in the uterus during this period. This prompted us to examine the roles of two negative growth-regulatory genes, cyclin G1 and cyclin G2, in the periimplantation mouse uterus. We show that cyclin G1 and cyclin G2 genes are differentially regulated in the uterus during this period (d 1-8 of pregnancy) in a spatiotemporal manner. The results suggest that cyclin G1 is primarily associated with epithelial cell differentiation before implantation and stromal cell proliferation and differentiation during decidualization, whereas cyclin G2 is associated with terminal differentiation and apoptosis of the luminal epithelial and stromal cells at the site of blastocyst after implantation. Pharmacological and genetic studies provide evidence that the expression of cyclin G1, not cyclin G2, is regulated by progesterone via its nuclear receptor. Furthermore, the expression of these genes is aberrantly up-regulated in homeo box A-10 mutant uteri, suggesting that cyclin G1 and cyclin G2 genes act as downstream targets of homeobox A-10 and negatively impact uterine cell proliferation. Collectively, our present and previous studies suggest that negative cell cycle regulators collaborate with growth-promoting regulators in regulating uterine cell-specific proliferation, differentiation, and apoptosis relevant to implantation and decidualization.

Animals↗