Control of Spermatogenesis in Mice by the Cyclin D-Dependent Kinase Inhibitors p18Ink4c and p19Ink4d

ABSTRACT Male mice lacking both the Ink4c and Ink4dgenes, which encode two inhibitors of D-type cyclin-dependent kinases (Cdks), are infertile, whereas female fecundity is unaffected. Both p18Ink4c and p19Ink4d are expressed in the seminiferous tubules of postnatal wild-type mice, being largely confined to postmitotic spermatocytes undergoing meiosis. Their combined loss is associated with the delayed exit of spermatogonia from the mitotic cell cycle, leading to the retarded appearance of meiotic cells that do not properly differentiate and instead undergo apoptosis at an increased frequency. As a result, mice lacking bothInk4c and Ink4d produce few mature sperm, and the residual spermatozoa have reduced motility and decreased viability. Whether or not Ink4d is present, animals lackingInk4c develop hyperplasia of interstitial testicular Leydig cells, which produce reduced levels of testosterone. The anterior pituitary of fertile mice lacking Ink4c or infertile mice doubly deficient for Ink4c and Ink4d produces normal levels of luteinizing hormone (LH). Therefore, the failure of Leydig cells to produce testosterone is not secondary to defects in LH production, and reduced testosterone levels do not account for infertility in the doubly deficient strain. By contrast,Ink4d-null or double-null mice produce elevated levels of follicle-stimulating hormone (FSH). Because Ink4d-null mice are fertile, increased FSH production by the anterior pituitary is also unlikely to contribute to the sterility observed inInk4c/Ink4d double-null males. Our data indicate that p18Ink4c and p19Ink4d are essential for male fertility. These two Cdk inhibitors collaborate in regulating spermatogenesis, helping to ensure mitotic exit and the normal meiotic maturation of spermatocytes.

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Manipulating the onset of cell cycle withdrawal in differentiated erythroid cells with cyclin-dependent kinases and inhibitors

Blood ◽

10.1182/blood.v96.8.2755 ◽

2000 ◽

Vol 96 (8) ◽

pp. 2755-2764 ◽

Cited By ~ 29

Author(s):

Igor Matushansky ◽

Farshid Radparvar ◽

Arthur I. Skoultchi

Keyword(s):

Cell Cycle ◽

Terminal Differentiation ◽

Cdk Inhibitors ◽

Cyclin D ◽

Erythroid Cells ◽

Stable Transfectants ◽

Cyclin Dependent Kinases ◽

Erythroleukemia Cells ◽

Murine Erythroleukemia ◽

Murine Erythroleukemia Cells

Abstract Terminal differentiation of erythroid cells results in terminal cell divisions followed by irreversible cell cycle withdrawal of hemoglobinized cells. The mechanisms leading to cell cycle withdrawal were assessed in stable transfectants of murine erythroleukemia cells, in which the activities of cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs) could be tightly regulated during differentiation. Cell cycle withdrawal of differentiating cells is mediated by induction of several CDKIs, thereby leading to inhibition of CDK2 and CDK4. Manipulation of CDK activity in differentiating cells demonstrates that the onset of cell cycle withdrawal can be either greatly accelerated or greatly delayed without affecting hemoglobin levels. Extending the proliferation of differentiating cells requires the synergistic action of CDK2 and CDK4. Importantly, CDK6 cannot substitute for CDK4 in this role, which demonstrates that the 2 cyclin D–dependent kinases are functionally different. The results show that differentiating hemoglobinized cells can be made to proliferate far beyond their normal capacity to divide.

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Manipulating the onset of cell cycle withdrawal in differentiated erythroid cells with cyclin-dependent kinases and inhibitors

Blood ◽

10.1182/blood.v96.8.2755.h8002755_2755_2764 ◽

2000 ◽

Vol 96 (8) ◽

pp. 2755-2764 ◽

Cited By ~ 5

Author(s):

Igor Matushansky ◽

Farshid Radparvar ◽

Arthur I. Skoultchi

Keyword(s):

Cell Cycle ◽

Terminal Differentiation ◽

Cdk Inhibitors ◽

Cyclin D ◽

Erythroid Cells ◽

Stable Transfectants ◽

Cyclin Dependent Kinases ◽

Erythroleukemia Cells ◽

Murine Erythroleukemia ◽

Murine Erythroleukemia Cells

Terminal differentiation of erythroid cells results in terminal cell divisions followed by irreversible cell cycle withdrawal of hemoglobinized cells. The mechanisms leading to cell cycle withdrawal were assessed in stable transfectants of murine erythroleukemia cells, in which the activities of cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs) could be tightly regulated during differentiation. Cell cycle withdrawal of differentiating cells is mediated by induction of several CDKIs, thereby leading to inhibition of CDK2 and CDK4. Manipulation of CDK activity in differentiating cells demonstrates that the onset of cell cycle withdrawal can be either greatly accelerated or greatly delayed without affecting hemoglobin levels. Extending the proliferation of differentiating cells requires the synergistic action of CDK2 and CDK4. Importantly, CDK6 cannot substitute for CDK4 in this role, which demonstrates that the 2 cyclin D–dependent kinases are functionally different. The results show that differentiating hemoglobinized cells can be made to proliferate far beyond their normal capacity to divide.

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The Renaissance of Cyclin Dependent Kinase Inhibitors

Cancers ◽

10.3390/cancers14020293 ◽

2022 ◽

Vol 14 (2) ◽

pp. 293

Author(s):

Tobias Ettl ◽

Daniela Schulz ◽

Richard Josef Bauer

Keyword(s):

Cell Cycle Progression ◽

Molecular Mechanisms ◽

Kinase Inhibitors ◽

Tumor Therapy ◽

Tumor Development ◽

Therapeutic Benefit ◽

Cdk Inhibitors ◽

Altered Expression ◽

Cyclin Dependent Kinases ◽

Targeted Inhibition

Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired cell proliferation, a hallmark of cancer. In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor entities. Their success is reflected in clinical approvals of specific CDK4/6 inhibitors for breast cancer. This review provides a detailed insight into the molecular mechanisms of CDKs as well as a general overview of CDK inhibition. It also summarizes the latest research approaches and current advances in the treatment of head and neck cancer with CDK inhibitors. Instead of monotherapies, combination therapies with CDK inhibitors may especially provide promising results in tumor therapy. Indeed, recent studies have shown a synergistic effect of CDK inhibition together with chemo- and radio- and immunotherapy in cancer treatment to overcome tumor evasion, which may lead to a renaissance of CDK inhibitors.

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Functions of TAM RTKs in regulating spermatogenesis and male fertility in mice

Reproduction ◽

10.1530/rep-09-0101 ◽

2009 ◽

Vol 138 (4) ◽

pp. 655-666 ◽

Cited By ~ 36

Author(s):

Yongmei Chen ◽

Huizhen Wang ◽

Nan Qi ◽

Hui Wu ◽

Weipeng Xiong ◽

...

Keyword(s):

Germ Cells ◽

Sertoli Cells ◽

Tyrosine Kinases ◽

Male Fertility ◽

Leydig Cells ◽

Seminiferous Tubules ◽

Wild Type ◽

Male Sterile ◽

Triple Mutant ◽

Insight Into

Mice lacking TYRO3, AXL and MER (TAM) receptor tyrosine kinases (RTKs) are male sterile. The mechanism of TAM RTKs in regulating male fertility remains unknown. In this study, we analyzed in more detail the testicular phenotype of TAM triple mutant (TAM−/−) mice with an effort to understand the mechanism. We demonstrate that the three TAM RTKs cooperatively regulate male fertility, and MER appears to be more important than AXL and TYRO3. TAM−/− testes showed a progressive loss of germ cells from elongated spermatids to spermatogonia. Young adult TAM−/− mice exhibited oligo-astheno-teratozoospermia and various morphological malformations of sperm cells. As the mice aged, the germ cells were eventually depleted from the seminiferous tubules. Furthermore, we found that TAM−/− Sertoli cells have an impaired phagocytic activity and a large number of differentially expressed genes compared to wild-type controls. By contrast, the function of Leydig cells was not apparently affected by the mutation of TAM RTKs. Therefore, we conclude that the suboptimal function of Sertoli cells leads to the impaired spermatogenesis in TAM−/− mice. The results provide novel insight into the mechanism of TAM RTKs in regulating male fertility.

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Haploinsufficiency of p18INK4c Sensitizes Mice to Carcinogen-Induced Tumorigenesis

Molecular and Cellular Biology ◽

10.1128/mcb.23.4.1269-1277.2003 ◽

2003 ◽

Vol 23 (4) ◽

pp. 1269-1277 ◽

Cited By ~ 71

Author(s):

Feng Bai ◽

Xin-Hai Pei ◽

Virginia L. Godfrey ◽

Yue Xiong

Keyword(s):

Wide Spectrum ◽

Tumor Development ◽

Pituitary Tumors ◽

Cdk Inhibitors ◽

Cyclin D ◽

Wild Type Allele ◽

Cyclin Dependent Kinase ◽

Loss Of Function ◽

Wild Type ◽

Targeted Deletion

ABSTRACT The INK4 family of cyclin-dependent kinase (CDK) inhibitors negatively regulates cyclin D-dependent CDK4 and CDK6 and thereby retains the growth-suppressive function of Rb family proteins. Mutations in the CDK4 gene conferring INK4 resistance are associated with familial and sporadic melanoma in humans and result in a wide spectrum of tumors in mice. Whereas loss of function of other INK4 genes in mice leads to little or no tumor development, targeted deletion of p18 INK4c causes spontaneous pituitary tumors and lymphoma late in life. Here we show that treatment of p18 null and heterozygous mice with a chemical carcinogen resulted in tumor development at an accelerated rate. The remaining wild-type allele of p18 was neither mutated nor silenced in tumors derived from heterozygotes. Hence, p18 is a haploinsufficient tumor suppressor in mice.

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Mice Deficient for Testis-Brain RNA-Binding Protein Exhibit a Coordinate Loss of TRAX, Reduced Fertility, Altered Gene Expression in the Brain, and Behavioral Changes

Molecular and Cellular Biology ◽

10.1128/mcb.23.18.6419-6434.2003 ◽

2003 ◽

Vol 23 (18) ◽

pp. 6419-6434 ◽

Cited By ~ 69

Author(s):

Vargheese Chennathukuzhi ◽

Joel M. Stein ◽

Ted Abel ◽

Stacy Donlon ◽

Shicheng Yang ◽

...

Keyword(s):

Gene Expression ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Mitotic Cell ◽

Seminiferous Tubules ◽

Factor X ◽

Wild Type ◽

Altered Gene Expression ◽

Altered Gene

ABSTRACT Testis-brain RNA-binding protein (TB-RBP), the mouse orthologue of the human protein Translin, is a widely expressed and highly conserved protein with proposed functions in chromosomal translocations, mitotic cell division, and mRNA transport and storage. To better define the biological roles of TB-RBP, we generated mice lacking TB-RBP. Matings between heterozygotes gave rise to viable, apparently normal homozygous mutant mice at a normal Mendelian ratio. The TB-RBP-related and -interacting protein Translin-associated factor X was reduced to 50% normal levels in heterozygotes and was absent in TB-RBP-null animals. The null mice were 10 to 30% smaller than their wild-type or heterozygote littermates at birth and remained so to about 6 to 9 months of age, showed normal B- and T-cell development, and accumulated visceral fat. TB-RBP-null male mice were fertile and sired offspring but had abnormal seminiferous tubules and reduced sperm counts. Null female mice were subfertile and had reduced litter sizes. Microarray analysis of total brain RNA from null and wild-type mice revealed an altered gene expression profile with the up-regulation of 14 genes and the down-regulation of 217 genes out of 12,473 probe sets. Numerous neurotransmitter receptors and ion channels, including γ-aminobutyric acid A receptor α1 and glutamate receptor α3, were strongly down-regulated. Behavioral abnormalities were also seen. Compared to littermates, the TB-RBP-null mice appeared docile and exhibited reduced Rota-Rod performance.

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CDK4 and CDK6 kinases: From basic science to cancer therapy

Science ◽

10.1126/science.abc1495 ◽

2022 ◽

Vol 375 (6577) ◽

Author(s):

Anne Fassl ◽

Yan Geng ◽

Piotr Sicinski

Keyword(s):

Breast Cancer ◽

Cell Division ◽

Cancer Therapy ◽

Cancer Cell ◽

Cancer Progression ◽

Basic Science ◽

Cdk Inhibitors ◽

Cyclin D ◽

Cyclin Dependent Kinases ◽

New Concepts

Targeting cyclin-dependent kinases Cyclin-dependent kinases (CDKs), in complex with their cyclin partners, modulate the transition through phases of the cell division cycle. Cyclin D–CDK complexes are important in cancer progression, especially for certain types of breast cancer. Fassl et al . discuss advances in understanding the biology of cyclin D–CDK complexes that have led to new concepts about how drugs that target these complexes induce cancer cell cytostasis and suggest possible combinations to widen the types of cancer that can be treated. They also discuss progress in overcoming resistance to cyclin D–CDK inhibitors and their possible application to diseases beyond cancer. —GKA

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Alkaloids as Anticancer Agents: A Review of Chinese Patents in Recent 5 Years

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892815666200131120618 ◽

2020 ◽

Vol 15 (1) ◽

pp. 2-13 ◽

Cited By ~ 3

Author(s):

Hongyu Tao ◽

Ling Zuo ◽

Huanli Xu ◽

Cong Li ◽

Gan Qiao ◽

...

Keyword(s):

Anticancer Activity ◽

Anticancer Agents ◽

Kinase Inhibitors ◽

Protein Kinase Inhibitors ◽

Cdk Inhibitors ◽

Comprehensive Overview ◽

P53 Expression ◽

Study Results

Background: In recent years, many novel alkaloids with anticancer activity have been found in China, and some of them are promising for developing as anticancer agents. Objective: This review aims to provide a comprehensive overview of the information about alkaloid anticancer agents disclosed in Chinese patents, and discusses their potential to be developed as anticancer drugs used clinically. Methods: Anticancer alkaloids disclosed in Chinese patents in recent 5 years were presented according to their mode of actions. Their study results published on PubMed, and SciDirect databases were presented. Results: More than one hundred anticancer alkaloids were disclosed in Chinese patents and their mode of action referred to arresting cell cycle, inhibiting protein kinases, affecting DNA synthesis and p53 expression, etc. Conclusion: Many newly found alkaloids displayed potent anticancer activity both in vitro and in vivo, and some of the anticancer alkaloids acted as protein kinase inhibitors or CDK inhibitors possess the potential for developing as novel anticancer agents.

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Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction

Cancers ◽

10.3390/cancers13030576 ◽

2021 ◽

Vol 13 (3) ◽

pp. 576

Author(s):

Sofia Giacosa ◽

Catherine Pillet ◽

Irinka Séraudie ◽

Laurent Guyon ◽

Yann Wallez ◽

...

Keyword(s):

High Throughput Screening ◽

Renal Carcinoma ◽

Kinase Inhibitors ◽

Ex Vivo ◽

Cancer Therapeutics ◽

Carcinoma Cells ◽

Wild Type ◽

Cell Renal Cell Carcinoma ◽

Von Hippel Lindau ◽

Renal Carcinoma Cells

Kinase-targeted agents demonstrate antitumor activity in advanced metastatic clear cell renal cell carcinoma (ccRCC), which remains largely incurable. Integration of genomic approaches through small-molecules and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. The 786-O cell line represents a model for most ccRCC that have a loss of functional pVHL (von Hippel-Lindau). A multiplexed assay was used to study the cellular fitness of a panel of engineered ccRCC isogenic 786-O VHL− cell lines in response to a collection of targeted cancer therapeutics including kinase inhibitors, allowing the interrogation of over 2880 drug–gene pairs. Among diverse patterns of drug sensitivities, investigation of the mechanistic effect of one selected drug combination on tumor spheroids and ex vivo renal tumor slice cultures showed that VHL-defective ccRCC cells were more vulnerable to the combined inhibition of the CK2 and ATM kinases than wild-type VHL cells. Importantly, we found that HIF-2α acts as a key mediator that potentiates the response to combined CK2/ATM inhibition by triggering ROS-dependent apoptosis. Importantly, our findings reveal a selective killing of VHL-deficient renal carcinoma cells and provide a rationale for a mechanism-based use of combined CK2/ATM inhibitors for improved patient care in metastatic VHL-ccRCC.

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