Background DNA damage response has been clearly described as an anti-cancer barrier in early huma... more Background DNA damage response has been clearly described as an anti-cancer barrier in early human tumorigenesis. Moreover, interestingly, testicular germ cell tumors (TGCTs) have been reported to lack the DNA Damage Response (DDR) pathway activation. CCDC6 is a pro-apoptotic phosphoprotein substrate of the kinase ataxia telangectasia mutated (ATM) able to sustain DNA damage checkpoint in response to genotoxic stress and is commonly rearranged in malignancies upon fusion with different partners. In our study we sought to determine whether CCDC6 could have a role in the patho-genesis of testicular germ cell tumors. Methods To achieve this aim, analysis for CCDC6 expression has been evaluated on serial sections of the mouse testis by immunohistochemistry and on separate populations of murine testicular cells by western blot. Next, the resistance to DNA damage-induced apoptosis and the production of reactive oxygen species has been investigated in GC1 cells, derived from immortalized t...
CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhanc... more CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhances tumour progression. In primary tumours, the impaired function of CCDC6 protein has been ascribed to CCDC6 rearrangements and to somatic mutations in several neoplasia. Recently, low levels of CCDC6 protein, in NSCLC, have been correlated with tumor prognosis. However, the mechanisms responsible for the variable levels of CCDC6 in primary tumors have not been described yet.We show that CCDC6 turnover is regulated in a cell cycle dependent manner. CCDC6 undergoes a cyclic variation in the phosphorylated status and in protein levels that peak at G2 and decrease in mitosis. The reduced stability of CCDC6 in the M phase is dependent on mitotic kinases and on degron motifs that are present in CCDC6 and direct the recruitment of CCDC6 to the FBXW7 E3 Ubl. The de-ubiquitinase enzyme USP7 appears responsible of the fine tuning of the CCDC6 stability, affecting cells behaviour and drug response...
To assess whether the presence of a gestational sac or the width of the endometrium, can be used ... more To assess whether the presence of a gestational sac or the width of the endometrium, can be used to predict the outcome of expectant management for an incomplete, first-trimester miscarriage, and to determine an appropriate schedule for follow-up visits. Consecutive women with a spontaneous miscarriage, who were attending an early pregnancy assessment unit. Transvaginal ultrasonography was used at the first visit to identify those women with an incomplete miscarriage--defined as the presence of heterogeneous products of conception within the uterus and distinguishable from a missed miscarriage or an anembryonic pregnancy. The sonographic end-points were the presence of a gestational sac or the thickness of the endometrium. All subjects were offered the choice of surgical evacuation of the uterus under general anesthesia or expectant management with a follow-up visit within a few days of the cessation of transvaginal bleeding, or weekly monitoring for 4-5 weeks. The main outcome measures were the number of women with a complete miscarriage (defined as the absence of transvaginal bleeding and an endometrial thickness of < 15 mm without surgical intervention) and the proportion of women completing their miscarriage within each week of management. Of the 312 women who participated, 234 (75%) chose expectant management; of these 13 were lost to follow-up leaving data from 221 for analysis. Two-hundred and one (91%) completed their miscarriage without intervention; the mean time from diagnosis to completion was 9 (range, 1-32) days. By the end of week 2, 184 women (83%) had miscarried. There was no statistically significant relationship between the initial presence of a gestational sac or endometrial thickness, and the success rate of expectant management. The odds of a woman completing a miscarriage spontaneously were 1 : 1 for week 1, 2 : 1 for week 2, 1 : 2 for week 3, and 1 : 5 for week 4. Twenty women had surgical treatment (19 elective with no serious prior complications, one emergency who was admitted to the accident and emergency department on day 21 of management). There were eight elective operations during week 1, and 11 over the following 3 weeks. Most women with an incomplete, spontaneous miscarriage chose expectant management and had a successful outcome. Neither the presence of a gestational sac, nor the endometrial thickness at diagnosis can be used to predict the likelihood of management failure. The current schedule of regular routine follow-up visits could be safely reduced to one or two fortnightly visits as appropriate, provided that patients have ready access to clinical advice by telephone.
The acetyl-transferase Tip60 might influence tumorigenesis in multiple ways. First, Tip60 is a co... more The acetyl-transferase Tip60 might influence tumorigenesis in multiple ways. First, Tip60 is a co-regulator of transcription factors that either promote or suppress tumorigenesis, such as Myc and p53. Second, Tip60 modulates DNA-damage response (DDR) signalling, and a DDR triggered by oncogenes can counteract tumour progression. Using E(mu)-myc transgenic mice that are heterozygous for a Tip60 gene (Htatip) knockout allele (hereafter denoted as Tip60+/- mice), we show that Tip60 counteracts Myc-induced lymphomagenesis in a haplo-insufficient manner and in a time window that is restricted to a pre- or early-tumoral stage. Tip60 heterozygosity severely impaired the Myc-induced DDR but caused no general DDR defect in B cells. Myc- and p53-dependent transcription were not affected, and neither were Myc-induced proliferation, activation of the ARF-p53 tumour suppressor pathway or the resulting apoptotic response. We found that the human TIP60 gene (HTATIP) is a frequent target for mono-a...
CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhanc... more CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhances tumour progression. In primary tumours, the impaired function of CCDC6 protein has been ascribed to CCDC6 rearrangements and to somatic mutations in several neoplasia. Recently, low levels of CCDC6 protein, in NSCLC, have been correlated with tumor prognosis. However, the mechanisms responsible for the variable levels of CCDC6 in primary tumors have not been described yet.We show that CCDC6 turnover is regulated in a cell cycle dependent manner. CCDC6 undergoes a cyclic variation in the phosphorylated status and in protein levels that peak at G2 and decrease in mitosis. The reduced stability of CCDC6 in the M phase is dependent on mitotic kinases and on degron motifs that are present in CCDC6 and direct the recruitment of CCDC6 to the FBXW7 E3 Ubl. The de-ubiquitinase enzyme USP7 appears responsible of the fine tuning of the CCDC6 stability, affecting cells behaviour and drug response...
Background DNA damage response has been clearly described as an anti-cancer barrier in early huma... more Background DNA damage response has been clearly described as an anti-cancer barrier in early human tumorigenesis. Moreover, interestingly, testicular germ cell tumors (TGCTs) have been reported to lack the DNA Damage Response (DDR) pathway activation. CCDC6 is a pro-apoptotic phosphoprotein substrate of the kinase ataxia telangectasia mutated (ATM) able to sustain DNA damage checkpoint in response to genotoxic stress and is commonly rearranged in malignancies upon fusion with different partners. In our study we sought to determine whether CCDC6 could have a role in the patho-genesis of testicular germ cell tumors. Methods To achieve this aim, analysis for CCDC6 expression has been evaluated on serial sections of the mouse testis by immunohistochemistry and on separate populations of murine testicular cells by western blot. Next, the resistance to DNA damage-induced apoptosis and the production of reactive oxygen species has been investigated in GC1 cells, derived from immortalized t...
CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhanc... more CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhances tumour progression. In primary tumours, the impaired function of CCDC6 protein has been ascribed to CCDC6 rearrangements and to somatic mutations in several neoplasia. Recently, low levels of CCDC6 protein, in NSCLC, have been correlated with tumor prognosis. However, the mechanisms responsible for the variable levels of CCDC6 in primary tumors have not been described yet.We show that CCDC6 turnover is regulated in a cell cycle dependent manner. CCDC6 undergoes a cyclic variation in the phosphorylated status and in protein levels that peak at G2 and decrease in mitosis. The reduced stability of CCDC6 in the M phase is dependent on mitotic kinases and on degron motifs that are present in CCDC6 and direct the recruitment of CCDC6 to the FBXW7 E3 Ubl. The de-ubiquitinase enzyme USP7 appears responsible of the fine tuning of the CCDC6 stability, affecting cells behaviour and drug response...
To assess whether the presence of a gestational sac or the width of the endometrium, can be used ... more To assess whether the presence of a gestational sac or the width of the endometrium, can be used to predict the outcome of expectant management for an incomplete, first-trimester miscarriage, and to determine an appropriate schedule for follow-up visits. Consecutive women with a spontaneous miscarriage, who were attending an early pregnancy assessment unit. Transvaginal ultrasonography was used at the first visit to identify those women with an incomplete miscarriage--defined as the presence of heterogeneous products of conception within the uterus and distinguishable from a missed miscarriage or an anembryonic pregnancy. The sonographic end-points were the presence of a gestational sac or the thickness of the endometrium. All subjects were offered the choice of surgical evacuation of the uterus under general anesthesia or expectant management with a follow-up visit within a few days of the cessation of transvaginal bleeding, or weekly monitoring for 4-5 weeks. The main outcome measures were the number of women with a complete miscarriage (defined as the absence of transvaginal bleeding and an endometrial thickness of < 15 mm without surgical intervention) and the proportion of women completing their miscarriage within each week of management. Of the 312 women who participated, 234 (75%) chose expectant management; of these 13 were lost to follow-up leaving data from 221 for analysis. Two-hundred and one (91%) completed their miscarriage without intervention; the mean time from diagnosis to completion was 9 (range, 1-32) days. By the end of week 2, 184 women (83%) had miscarried. There was no statistically significant relationship between the initial presence of a gestational sac or endometrial thickness, and the success rate of expectant management. The odds of a woman completing a miscarriage spontaneously were 1 : 1 for week 1, 2 : 1 for week 2, 1 : 2 for week 3, and 1 : 5 for week 4. Twenty women had surgical treatment (19 elective with no serious prior complications, one emergency who was admitted to the accident and emergency department on day 21 of management). There were eight elective operations during week 1, and 11 over the following 3 weeks. Most women with an incomplete, spontaneous miscarriage chose expectant management and had a successful outcome. Neither the presence of a gestational sac, nor the endometrial thickness at diagnosis can be used to predict the likelihood of management failure. The current schedule of regular routine follow-up visits could be safely reduced to one or two fortnightly visits as appropriate, provided that patients have ready access to clinical advice by telephone.
The acetyl-transferase Tip60 might influence tumorigenesis in multiple ways. First, Tip60 is a co... more The acetyl-transferase Tip60 might influence tumorigenesis in multiple ways. First, Tip60 is a co-regulator of transcription factors that either promote or suppress tumorigenesis, such as Myc and p53. Second, Tip60 modulates DNA-damage response (DDR) signalling, and a DDR triggered by oncogenes can counteract tumour progression. Using E(mu)-myc transgenic mice that are heterozygous for a Tip60 gene (Htatip) knockout allele (hereafter denoted as Tip60+/- mice), we show that Tip60 counteracts Myc-induced lymphomagenesis in a haplo-insufficient manner and in a time window that is restricted to a pre- or early-tumoral stage. Tip60 heterozygosity severely impaired the Myc-induced DDR but caused no general DDR defect in B cells. Myc- and p53-dependent transcription were not affected, and neither were Myc-induced proliferation, activation of the ARF-p53 tumour suppressor pathway or the resulting apoptotic response. We found that the human TIP60 gene (HTATIP) is a frequent target for mono-a...
CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhanc... more CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhances tumour progression. In primary tumours, the impaired function of CCDC6 protein has been ascribed to CCDC6 rearrangements and to somatic mutations in several neoplasia. Recently, low levels of CCDC6 protein, in NSCLC, have been correlated with tumor prognosis. However, the mechanisms responsible for the variable levels of CCDC6 in primary tumors have not been described yet.We show that CCDC6 turnover is regulated in a cell cycle dependent manner. CCDC6 undergoes a cyclic variation in the phosphorylated status and in protein levels that peak at G2 and decrease in mitosis. The reduced stability of CCDC6 in the M phase is dependent on mitotic kinases and on degron motifs that are present in CCDC6 and direct the recruitment of CCDC6 to the FBXW7 E3 Ubl. The de-ubiquitinase enzyme USP7 appears responsible of the fine tuning of the CCDC6 stability, affecting cells behaviour and drug response...
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Papers by Chiara Luise