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In vivo studies of cell cycle regulating proteins in rats during liver regeneration and during promotion of liver carcinogenesis
Södertörn University, School of Chemistry, Biology, Geography and Environmental Science. Karolinska Institutet.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There are more than one hundred different types of cancer in humans. However, the major platform for all types of cancer is automous and uncontrolled cell division and though most types of cancer are possible to treat and cure by surgery, chemical therapy or irradiation, more efficient and less toxic therapies are urgently needed. In the modern society we are exposed to more toxins than ever. The liver, as main detoxifier of our blood, is handling many hazardous compounds. Unfortunately, after being metabolised in the liver, many of these are able to act as promoters for one of the most lethal types of cancer, the hepatocellular carcinoma (HCC). Previous studies demonstrated that nuclear accumulation of p53 and other proteins is essential for efficient tumor suppression. Based on this, the aim of the study was to investigate whether altered localization and/or p53 protein expression is an early event in tumor development in liver that possibly contributes to the growth advantage of initiated hepatocytes. We also addressed the question of which impact 2-AAF exerts on cell cycle at early stages of tumor promotion. Preneoplastic foci were induced in rat liver by treatment with diethylnitroseamin (DEN), combined with either of the four tumor promoters, 2acetylaminofluorene, 17-alpha ethinylestradiol, choline-deficient diet or deoxycholic acid. This was combined with 2/3 partial hepatectomy as a proliferative stimulus. The immunohistochemical results showed that all four promoters decreased the focal expression of p53 and p21, two proteins known to inhibit replication upon DNA damage, in both nucleus and cytoplasm. In contrast, in surrounding tissue increased nuclear levels of p53 and p21 was observed. These data suggest that deregulation of p53 and p21 might be a common feature occurring early during promotion of HCC in vivo. We also found that treatment with 2-AAF prevented the induction of nuclear p53 in foci in response to gamma-irradiation in initiated male Wistar rats, which correlated with increased cytoplasmic expression of Mdm2 and Bcl-2 in foci. It is possible that complex formation with elevated Mdm2 together with increased Bcl-2 protein expression contributes to the sequestration and inactivation of p53 in cytoplasm. Growth signalling in regenerating liver was studied in non-initiated rats subjected to the tumor promoter 2-AAF. We found that 2-AAF exercise an almost complete mitoinhibitory effect in synchronised hepatocytes. Nuclear levels of cdk 4, cyclin D3, cyclin E, p53, p 130 and pRb were increased while the levels of PCNA, cdk 2, E2F- 1, -3 and -4 were decreased. Furthermore, both nuclear and cytoplasmic expression of cyclin A and - B proteins was lost. Finally, we found that p107 a member of the Rb-family and necessary for S-phase progression, but not pRB was increased in normal regenerating liver. In mitoinhibited liver the expression level of these two proteins was rather the opposit indicating slightly different roles for pRb and p107 during regeneration and cell cycle control, at least in this animal model.

Place, publisher, year, edition, pages
Stockholm: Karolinska Instiutet , 2004. , 44 p.
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:sh:diva-32063ISBN: 91-7349-980-3 (print)OAI: oai:DiVA.org:sh-32063DiVA: diva2:1074538
Public defence
2004-06-10, Hörsalen, Novum plan 4, Huddinge, 09:30 (English)
Opponent
Supervisors
Available from: 2017-02-15 Created: 2017-02-15 Last updated: 2017-02-15Bibliographically approved
List of papers
1. Tumor promotion in rat liver: low nuclear expression of p53 and p21 in preneoplastic foci compared with surrounding hepatocytes
Open this publication in new window or tab >>Tumor promotion in rat liver: low nuclear expression of p53 and p21 in preneoplastic foci compared with surrounding hepatocytes
(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Identifiers
urn:nbn:se:sh:diva-32064 (URN)
Note

Som manuskript i avhandling. As manuscript in dissertation.

Available from: 2017-02-15 Created: 2017-02-15 Last updated: 2017-02-15Bibliographically approved
2. Loss of nuclear p53 protein in preneoplastic rat hepatocytes is accompanied by Mdm2 and Bcl-2 overexpression and by defective response to DNA damage in vivo
Open this publication in new window or tab >>Loss of nuclear p53 protein in preneoplastic rat hepatocytes is accompanied by Mdm2 and Bcl-2 overexpression and by defective response to DNA damage in vivo
Show others...
2000 (English)In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 32, no 4, 701-710 p.Article in journal (Refereed) Published
National Category
Natural Sciences
Identifiers
urn:nbn:se:sh:diva-5880 (URN)10.1053/jhep.2000.17660 (DOI)000089618700003 ()11003613 (PubMedID)
Available from: 2011-02-01 Created: 2011-02-01 Last updated: 2017-02-15Bibliographically approved
3. Inhibition of in vivo rat liver regeneration by 2-acetylaminofluorene affects the regulation of cell cycle-related proteins
Open this publication in new window or tab >>Inhibition of in vivo rat liver regeneration by 2-acetylaminofluorene affects the regulation of cell cycle-related proteins
1998 (English)In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 27, no 3, 691-696 p.Article in journal (Refereed) Published
Abstract [en]

The effects of dietary 2-acetylaminofluorene (2-AAF) on cell cycle-related proteins was studied in regenerating livers from male Wistar rats, The levels of cyclins, cyclin dependent kinases (cdks), and related proteins were studied at different times during the first cell cycle after partial hepatectomy (PH). The frequency of proliferation cell nuclear antigen (PCNA)-positive nuclei, a marker of S phase progression, was almost zero during the first 27 hours after PH in the mitoinhibited 2-AAF-treated rats, while about 50% of the nuclei were labeled 24 hours after PH in control animals. Accordingly, Western blot tests showed markedly elevated PCNA protein levels from 18 hours to the end of S phase in untreated animals but no upregulation in response to 2-AAF. Compared with control animals, animals treated with 2-AAF showed increased levels of cdk 4 and cyclin D-3 from 12 and 15 hours after PH, respectively, and altered cyclicity in cyclin Dg expression. No effects on cyclin E were observed, while the increase in cdk 2 levels in control animals during late G(1)/S (15-27 hours) was abolished by 2-AAF. p53 was induced by 2-AAF treatment during the same period, with a peak at 24 hours. The protein detected with p21 antibodies was highly expressed in unstimulated hepatocytes in control animals, and further increased by 2-AAF. The expression was sustained until 15 hours after PH in control rats while 2-AAF-treated animals lacked detectable protein during this period; however, a transient increase was observed at 21 hours, Thus, 2-AAF affects several parameters of cell cycle regulation of possible relevance for its inhibitory effects on hepatocyte proliferation in vivo.

National Category
Biological Sciences
Identifiers
urn:nbn:se:sh:diva-32062 (URN)10.1002/hep.510270309 (DOI)000072249000009 ()9500696 (PubMedID)2-s2.0-0031913873 (ScopusID)
Available from: 2017-02-15 Created: 2017-02-15 Last updated: 2017-02-15Bibliographically approved
4. Mitoinhibitory effects of the tumor promoter 2-acetylaminofluorene in rat liver: loss of E2F-1 and E2F-3 expression and cdk 2 kinase activity in late G1
Open this publication in new window or tab >>Mitoinhibitory effects of the tumor promoter 2-acetylaminofluorene in rat liver: loss of E2F-1 and E2F-3 expression and cdk 2 kinase activity in late G1
2004 (English)In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 40, no 6, 957-962 p.Article in journal (Refereed) Published
National Category
Natural Sciences
Identifiers
urn:nbn:se:sh:diva-5879 (URN)10.1016/j.jhep.2004.02.028 (DOI)000221979400012 ()15158336 (PubMedID)2-s2.0-2542498042 (ScopusID)
Available from: 2011-02-01 Created: 2011-02-01 Last updated: 2017-02-15Bibliographically approved

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