Differential Expression Of Cyclin D1 Research Articles

Differential expression of cyclin D1, Ki‑67, pRb, and p53 in psoriatic skin lesions and normal skin.

Psoriasis is a hyperproliferative inflammatory skin disease; therefore, it is highly likely that psoriatic skin lesions may transform into malignancies. However, malignant transformation is not common. We performed immunohistochemical studies using anti-cyclin D1, anti-cyclin E, anti-pRb, anti-p53, anti-p16INK4a, and anti-Ki-67 antibodies in normal skin, psoriatic epidermal tissue, and squamous cell carcinoma (SCC) tissue. Furthermore, western blot analysis and immunohistochemical staining were performed to ascertain differences in cyclin D1, cyclin E, pRb, and Ki-67 expression before and after treatment for psoriasis. Cyclin D1 expression was higher in chronic psoriatic lesions than that in normal epidermis. Psoriasis lesions showed a strong intensity of positive nuclear staining for cyclin D1 among several normally stained nuclei in the basal layer. Cyclin E expression in psoriasis was stronger in the granular and spinous layer than in the normal epidermis. Expression levels of pRb and p53 were found to be higher in the psoriasis group compared with the normal epidermis. Total basal layer cell counts for p53WT expression were found to be significantly higher in the psoriasis group compared with the normal group. However, p16 expression was very weak in the normal and psoriasis groups compared with that in the SCC group. Ki-67 immunoreactivity was significantly higher in psoriasis compared with normal epidermis and was similar with that in the SCC group. According to immunohistochemistry and immunoblot analysis, the expression levels of cyclin D1, cyclin E, pRb, and Ki-67 in psoriasis lesions decreased after treatment and were similar with those in the normal group. Thus, increased expression of cyclin D1 and cyclin E may be involved in cell cycle progression in psoriatic epidermis, and pRb and p53 may play important roles in the prevention of malignant transformation under the hyperproliferative state in psoriasis.

Differential expression of cyclin D1 in keratin-producing odontogenic cysts.

Objetives: The aim of the present study was to analyze the expression levels of Cyclin D1 (CCD1), a nuclear protein that plays a crucial role in cell cycle progression, in a series of keratin-producing odontogenic cysts. Study Design: A total of 58 keratin-producing odontogenic cysts, diagnosed over ten years and classified according to the WHO 2005 criteria, were immunohistochemically analyzed in terms of CCD1 expression, which was quantified in the basal, suprabasal and intermediate/superficial epithelial compartments. The extent of immunostaining was measured as a proportion of total epithelial thickness. Quantified immunohistochemical data were correlated with clinicopathological features and clinical recurrence. Results: Keratin-producing odontogenic cysts were classified as 6 syndromic keratocystic odontogenic tumors (S-KCOT), 40 sporadic or non-syndromic KCOT (NS-KCOT) and 12 orthokeratinized odontogenic cysts (OOC). Immunohistochemically, CCD1 staining was evident predominantly in the parabasal region of all cystic lesions, but among-lesion differences were apparent, showing a clear expansion of parabasal compartment especially in the S-KCOT, followed to a lesser extent in the NS-KCOT, and being much more reduced in the OOC, which had the greatest average epithelial thickness. Conclusions: The differential expression of CCD1 noted in the present study suggests that dysregulation of cell cycle progression from G1 to the S phase contributes to the different aggressiveness of these lesions. However, CCD1 expression levels did not predict NS-KCOT recurrence, which is likely influenced by factors unrelated to lesion biology. Key words:Keratin-producing odontogenic cyst, keratocyst, keratocystic odontogenic tumor, nevoid basal cell carcinoma syndrome, orthokeratinized odontogenic cyst, cyclin D1, immunohistochemistry.

Cold tolerance of the invasive Carcinus maenas in the east Pacific: molecular mechanisms and implications for range expansion in a changing climate

Physiological studies have long been utilized to understand the role of environmental temperature in the distribution of native organisms within marine communities. For the invasive crab Carcinus maenas, temperature has been implicated as the main predictor of establishment success across temperate regions. Therefore, we determined whether the lower temperature tolerances of this non-native crab would restrict it from spreading farther poleward from a relatively new recipient environment. Cold tolerance capacity was determined in the laboratory by holding crabs sampled from Vancouver Island, British Columbia (BC)—near the present northern limit for the northeast Pacific metapopulation to an overwintering thermal profile generated from Sitka, Alaska, USA. These crabs were physiologically capable of overwintering north of their present range boundary. The cellular response to cold stress was investigated using two functional categories of the cellular stress response. We measured cyclin D1, a cell-cycle regulator, and Hsp70, a protein chaperone, after laboratory acclimation and acute cold stress on two populations of C. maenas from the west coast of North America that have disparate thermal histories (crabs sampled from CA or BC). We found site-specific differential expression of cyclin D1 after cold acclimation and cold shock, perhaps affecting invasion capacity in this species. Determining what physiological mechanisms are in place with respect to thermal tolerance and preference can give insight into what makes an invasive organism successful and aid in predicting probable distribution of such species within a new environment.

Differential expression of cyclin D1 in human pituitary tumors: relation to MIB-1 and p27/Kip1 labeling indices

BackgroundPituitary tumors are a common form of endocrine neoplasia. However few studies assessed the expression of the principal cyclin regulating checkpoint exit, cyclin D1. Cyclin D1 expression in pituitary tumors and its possible relation to MIB-1 and p27/Kip1 labeling indices (LIs) was explored. DesignWe studied a total of 199 pituitaries, including normal pituitaries (n=7), pituitary adenomas (n=187), and pituitary carcinoma (n=5). All tissues were tested as cores of archived tissue microarrays that were immunostained for cyclin D1, MIB-1 and p27 using a standard technique. Tissue cores were subjected to automated analysis to evaluate the staining LIs. ResultsNo cyclin D1 positive cells in the normal anterior pituitary gland was found. Sparse nuclear staining was noted in pituitary tumors. Higher expression of cyclin D1 was noted in pituitary carcinomas compared to adenomas (p<0.001), in non-functioning adenomas compared to functioning ones (p<0.001) in macroadenomas versus microadenomas (p=0.017) and in recurrent non recurrent adenomas (p<0.001). Cyclin D1 LI and MIB-1 LI were related among adenomas (p<0.001) and carcinomas (p=0.041). p27 LI was neither related to pituitary adenoma recurrence nor invasion. ConclusionsExpression of cyclin D1 in pituitary tumors is related to cell proliferation, recurrence, and metastatic potential. Nuclear cyclin D1 expression is a good marker of aggressive behavior in pituitary tumors.

AP-1 Regulates Cyclin D1 and c-MYC Transcription in an AKT-Dependent Manner in Response to mTOR Inhibition: Role of AIP4/Itch-Mediated JUNB Degradation

One mechanism by which AKT kinase-dependent hypersensitivity to mammalian target of rapamycin (mTOR) inhibitors is controlled is by the differential expression of cyclin D1 and c-MYC. Regulation of posttranscriptional processes has been demonstrated to be crucial in governing expression of these determinants in response to rapamycin. Our previous data suggested that cyclin D1 and c-MYC expression might additionally be coordinately regulated in an AKT-dependent manner at the level of transcription. Under conditions of relatively quiescent AKT activity, treatment of cells with rapamycin resulted in upregulation of cyclin D1 and c-MYC nascent transcription, whereas in cells containing active AKT, exposure repressed transcription. Promoter analysis identified AKT-dependent rapamycin responsive elements containing AP-1 transactivation sites. Phosphorylated c-JUN binding to these promoters correlated with activation of transcription whereas JUNB occupancy was associated with promoter repression. Forced overexpression of JunB or a conditionally active JunB-ER allele repressed cyclin D1 and c-MYC promoter activity in quiescent AKT-containing cells following rapamycin exposure. AIP4/Itch-dependent JUNB protein degradation was found to be markedly reduced in active AKT-containing cells compared with cells harboring quiescent AKT. Moreover, silencing AIP4/Itch expression or inhibiting JNK mediated AIP4 activity abrogated the rapamycin-induced effects on cyclin D1 and c-MYC promoter activities. Our findings support a role for the AKT-dependent regulation of AIP4/Itch activity in mediating the differential cyclin D1 and c-MYC transcriptional responses to rapamycin.

Differential Expression of Cyclin D1 in the Human Hair Follicle

The proliferation of keratinocytes in the hair follicle varies from slowly cycling, intermittently proliferating stem cells in the bulge to rapidly proliferating, transient cells in the bulb. To better understand the biological differences between these two compartments, we sought to identify differentially expressed genes using cDNA macroarray analysis. Cyclin D1 was one of 13 genes increased in the bulge compared to the bulb, and its differential expression was corroborated by quantitative real-time polymerase chain reaction (PCR) on the original samples. Using immunohistochemical staining, laser-capture microdissection (LCM) and quantitative real-time PCR, we localized cyclin D1 to the suprabasal cells of the telogen bulge and anagen outer root sheath (ORS). Surprisingly, cyclin D1, D2, and D3 were not detectable by immunohistochemistry in the rapidly proliferating hair-producing cells of the anagen bulb (matrix cells), while these cells were strongly positive for Ki-67 and retinoblastoma protein. In contrast, pilomatricoma, a tumor thought to be derived from matrix cells, was positive for cyclin D1, D2, and D3. Our results suggest that cyclin D1 may mediate the proliferation of stem cells in the bulge to more differentiated transient amplifying cells in the suprabasal ORS. In contrast, non-cyclin D1-proteins appear to control cell division of the highly proliferative bulb matrix cells. This non-cyclin D1-mediated proliferation may provide a protective mechanism against tumorigenesis, which is overridden in pilomatricomas. Our data also demonstrate that the combination of DNA macroarray, LCM and quantitative real-time PCR is a powerful approach for the study of gene expression in defined cell populations with limited starting material.

Programmed Cell Death (Apoptosis) and Its Role in the Pathogenesis of Lower Extremity Varicose Veins

The etiology of varicose veins remains elusive. We hypothesized that abnormal cell cycle events in the vein wall may contribute to changes in its structural integrity predisposing to varicosity development. Since cell cycle checkpoint controls are linked to the signaling and execution of apoptotic cascades, possibly apoptosis is a contributing factor in the pathophysiology of varicosities. The present study was designed to investigate whether programmed cell death varies in varicosities as compared to normal veins. Twenty-seven normal greater saphenous vein specimens were obtained from patients undergoing infrainguinal arterial bypass surgery, and 20 varicose vein specimens were retrieved from patients undergoing varicose vein excision. Apoptosis was detected by TUNEL assay. Expression of bcl-2 and cyclin D1 was noted by standard immunohistochemical techniques. Apoptotic cells were identified in 32 of the 47 specimens. Forty-eight percent of normal vein specimens displayed >3 apoptotic cells per 100 cells in the adventitia; 15% of the specimens of the varicose vein group showed such magnitude of apoptosis (p < 0.03). This increased apoptotic activity was not observed in media or intima of either vein group (p < 0.001). No significant difference in immunoreactivity to bcl-2 protein was observed in varicose vein specimens as compared to controls. Varicose vein specimens demonstrated increased nuclear expression of cyclin D1 whereas its cytoplasmic expression was significantly diminished (p </=0.02). These data show that programmed cell death is inhibited in varicose veins. Differential expression of cyclin D1 suggests that it may deregulate cell cycle events, thereby leading to varicosity formation.

Differential expression of cyclin D1 in breast papillary carcinomas and benign papillomas: an immunohistochemical study.

Distinguishing intraductal papilloma from papillary carcinoma of the breast can be difficult using histologic criteria. Since cyclin D1, a G1 cell-cycle regulatory protein, is detectable immunohistochemically in a subset of breast carcinomas but not in benign breast tissues, we hypothesized that cyclin D1 immunoreactivity may be a marker for identifying papillary carcinoma. Using an immunohistochemical method, we assessed for cyclin D1 expression in 8 breast papillomas and 6 papillary carcinomas, all of which were formalin fixed, routinely processed, and paraffin embedded. Cyclin D1 positivity also was compared with the overall proliferation rate, which was assessed by using the proliferation marker Ki-67. In each case, a 200-cell count was performed to obtain the percentage of cells positive for these 2 markers. The percentage of cyclin D1-positive cells was significantly higher in papillary carcinomas (89%+/-18%; range, 53%-98%) than in papillomas (8%+/-7%; range, 0%-19%). This difference was highly statistically significant (P < .0001). Although the difference in Ki-67 positivity between these 2 groups was also statistically significant (P = .01), separation of papillary carcinomas and papillomas by Ki-67 immunoreactivity was less clear because of overlapping values between groups: 13% +/-6%; range, 9% to 23% for papillary carcinomas versus 8%+/-2%; range, 6% to 12% for papillomas. These results support the notion that cyclin D1 is a useful marker for distinguishing breast papillomas from papillary carcinomas. The marker Ki-67 is also helpful, but is less useful than cyclin D1, owing to the overlap in Ki-67 results in papillomas and papillary carcinomas.

Differential expression of cyclin D1 in breast papillary carcinomas and benign papillomas: an immunohistochemical study.

○ Objectives.-Distinguishing intraductal papilloma from papillary carcinoma of the breast can be difficult using histologic criteria. Since cyclin D1, a G 1 cell-cycle regulatory protein, is detectable immunohistochemically in a subset of breast carcinomas but not in benign breast tissues, we hypothesized that cyclin D1 immunoreactivity may be a marker for identifying papillary carcinoma. Methods.-Using an immunohistochemical method, we assessed for cyclin D1 expression in 8 breast papillomas and 6 papillary carcinomas, all of which were formalin fixed, routinely processed, and paraffin embedded. Cyclin D1 positivity also was compared with the overall proliferation rate, which was assessed by using the proliferation marker Ki-67. In each case, a 200-cell count was performed to obtain the percentage of cells positive for these 2 markers. Results.-The percentage of cyclin D1-positive cells was significantly higher in papillary carcinomas (89% ± 18%; range, 53%-98%) than in papillomas (8% ± 7%; range, 0%-19%). This difference was highly statistically significant (P <.0001). Although the difference in Ki-67 positivity between these 2 groups was also statistically significant (P =.01), separation of papillary carcinomas and papillomas by Ki-67 immunoreactivity was less clear because of overlapping values between groups: 13% ± 6%; range, 9% to 23% for papillary carcinomas versus 8% ± 2%; range, 6% to 12% for papillomas. Conclusions.-These results support the notion that cyclin D1 is a useful marker for distinguishing breast papillomas from papillary carcinomas. The marker Ki-67 is also helpful, but is less useful than cyclin D1, owing to the overlap in Ki-67 results in papillomas and papillary carcinomas.

Differential Expression of Cyclin D1 in Mantle Cell Lymphoma and Other Non-Hodgkin's Lymphomas

Mantle-cell lymphomas are associated with a characteristic chromosomal translocation, t(11;14)(q13;q32). This translocation involves rearrangement of the bcl-1 proto-oncogene from chromosome 11 to the immunoglobulin heavy chain gene on chromosome 14, resulting in an overexpression of cyclin D1 mRNA (also known as bcl-1 and PRAD1). In the current study performed on paraffin-embedded tissue, cyclin D1 mRNA could be detected in 23 of 24 mantle-cell lymphomas by reverse transcription polymerase chain reaction (RT-PCR) whereas only 9 of 24 demonstrated a t(11;14) by PCR. However, we also found that cyclin D1 mRNA could be detected in the majority (11 of 17, 65%) of non-mantle-cell lymphomas and in a minority of atypical lymphoid hyperplasias (3 of 7, 43%). Cyclin D1 mRNA expression was not observed in floridly reactive lymph nodes (0 of 9) or in unstimulated lymph nodes (0 of 20), suggesting that it is a sensitive adjunct marker for malignant lymphoproliferative processes, but not specific for mantle-cell lymphoma. A semiquantitative RT-PCR assay was developed that compared the ratio of cyclin D1 to the constitutively expressed gene beta2-microglobulin. Using this assay on a limited number of our specimens, cyclin D1 overexpression in mantle-cell lymphoma could be reliably distinguished from its expression in other non-Hodgkin's lymphomas. This assay for cyclin D1 expression, designed for formalin-fixed, paraffin-embedded tissue, was a very sensitive and specific marker for mantle-cell lymphoma.