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Biomedical subjects

M Henriksson

Publications and source records attributed to M Henriksson.

At least 55 records · Page 3Linked to original sources
PubMed1995

Differential effects by Mad and Max on transformation by cellular and viral oncoproteins.

c-Myc is an essential component of the regulatory mechanisms controlling cell growth. Max is the obligatory partner of c-Myc for all its biological functions analysed to date. Recently two Max interacting proteins, Mad and Mxi1, have been identified. It has been suggested that these two proteins modulate c-Myc function, in the simplest model by competing with c-Myc for the interaction with Max. We have analysed different aspects of Mad function in comparison to Max. Native Mad/Max heterodimers bound specifically to a c-Myc/Max consensus DNA binding site. Furthermore Mad inhibited efficiently c-Myc, mutant p53, adenovirus E1a, or human papilloma virus type 16 transformation of rat embryo cells in cooperation with activated Ha-Ras. Myc transformed clones showed an increased cell cycle time and a reduced immortalization frequency after cotransfection with either mad or max. In contrast to Mad, Max did not inhibit E1a/Ha-Ras cotransformation but repressed c-Myc/Ha-Ras transformation efficiently. Mad delta N, an N-terminal deletion mutant of Mad, was as efficient in repressing c-Myc/Ha-Ras cotransformation as full length Mad but showed little inhibitory activity when assayed on E1a/Ha-Ras. Unlike wt Mad, Mad delta N had little effect on cell growth. Our data suggest that Mad affects cell growth at least in part by a c-Myc independent mechanism.

Animals↗
PubMed1995

Recent life events and completed suicide in bipolar affective disorder. A comparison with major depressive suicides.

While recent psychosocial stress has been shown to be associated with the initiation of both first and subsequent illness episodes in bipolar affective disorder, its relationship to completed suicide in bipolar disorder is not known. As a part of a nationwide psychological autopsy study, two populations representing all suicides in Finland in DSM-III-R bipolar disorder or unipolar major depression were comprehensively examined and compared. Recent life events were retrospectively examined by interviewing next of kin using a 32-item Recent Life Change Questionnaire. Life event data was available on 25 bipolar and 56 unipolar cases. In about two-thirds of both bipolar (64%) and unipolar (66%) victims, at least one life event was reported to have occurred during the last 3 months and in 42% of both groups during the final week. The events of bipolar victims were more commonly classified as possibly dependent on their own behaviour (bipolars 88% vs. unipolars 63%, P = 0.004). Among bipolars, more males than females had had recent life events (males 86% vs. females 37%, P = 0.03). The majority of completed suicides in both bipolar and unipolar affective disorders seem to be associated with recent psychosocial stress; however, the stressors are commonly likely to be dependent on the victim's behaviour.

Adult↗
PubMed1995

The amino-terminal phosphorylation sites of C-MYC are frequently mutated in Burkitt's lymphoma lines but not in mouse plasmacytomas and rat immunocytomas.

We sequenced the region encoding the amino-terminal phosphorylation sites of C-MYC in the Ig/MYC translocation-carrying Burkitt lymphomas (BL), mouse plasmacytomas (MPC) and rat immunocytomas (RIC). Mutations affecting the Thr-58 codon or the immediate flanking region were found in seven of the 10 in vitro propagated BL lines. No mutations were found in any of the eight BL biopsies analysed. Germ-line sequences were also found in six in vivo and five in vitro passaged MPCs and in four in vivo transplanted RICs. These findings indicate that mutations in this region do not represent a general phenomena in Ig/MYC translocation-carrying tumours, but may confer growth advantage on BL cells under continuous in vitro propagation.

Animals↗
PubMed1995

Project plan for studies on suicide, attempted suicide, and suicide prevention.

Completed and attempted suicide are major public health problems in most western countries. The importance of suicidal behavior as a health problem, particularly among adolescents and young adults, has been emphasized by the European Union, the WHO (Europe), as well as the Finnish authorities. Due to the exceptionally high suicide mortality, suicide prevention has been one of the main targets of Finnish health policy since the late 1980s. However, to develop feasible strategies for suicide prevention, better knowledge of the phenomenon of self-destruction is necessary. The Department of Mental Health of the National Public Health Institute has been actively involved in suicide research and the development of suicide strategies both in Finland and western Europe since 1986. The success is based on a long tradition of suicide research in Finland, the representative and reliable suicide data, a highly motivated research group, and also the necessary economic support by both the National Public Health Institute and the Finnish Academy. This article outlines our groups research plan for the next few years.

Adolescent↗
PubMed1995

Fear of AIDS and suicide in Finland: a review.

This review presents data on HIV epidemiology and suicide mortality, and summarizes studies on fear of AIDS in completed suicides in Finland. Finland has a low prevalence of HIV and a high suicide mortality. A 12-month nationwide suicide population, 1987-88 (n = 1397, all HIV negative) at the time of a sensational media campaign against HIV included 28 (2%) cases with fear of AIDS as a contributing factor. Triggers of fear could be classified in 20 cases: persistent symptoms in 10, casual sex contacts in eight, and a TV programme in two. The AIDS fear cases were younger, had more major depression and more health care contacts than the others. Suicidal fear and underlying depression were not being properly identified and treated. Despite recent improvement in media reporting, health education and identification of depression, clinical experience, help line calls and population surveys indicate that AIDS fear still persists in the population, but seems to be less often a contributing factor in committed suicides.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Suicide in psychotic major depression.

A sample of unipolar DSM-III-R major depressive suicide victims representing all suicides in current unipolar major depression within 1 year in Finland was carefully examined by psychological autopsy. The sample was divided into currently psychotic (n = 24) or non-psychotic (n = 46) subgroups, the psychotic subgroup was described and the two subgroups were compared. The majority (79%) of psychotic as well as nonpsychotic (87%) major depressive suicide victims were found to be complicated, comorbid cases. No major differences between the psychotic and nonpsychotic subgroups were found in sociodemographic features, comorbidity, clinical history or communication of suicide intent. However, the psychotic victims were more likely to have used violent suicide methods (88% vs. 59%).

Adolescent↗
PubMed1994

Regulation of transcription factors c-Myc, Max, and c-Myb by casein kinase II.

A number of transcription factors have been shown to be phosphorylated by casein kinase II (CKII). We have identified CKII phosphorylation sites in c-Myc, Max, and c-Myb which are phosphorylated in the cell. Whereas little evidence to any functional significance of the CKII sites in c-Myc has been obtained, phosphorylation of its heterodimeric partner Max alters DNA binding properties. CKII phosphorylation of Ser-2 and -11 in Max resulted in enhanced DNA binding kinetics of both Max/Max homo- and Myc/Max heterodimers without altering steady state binding. Replacing these serine by alanine residues and comparing the wild type with the mutant Max proteins in transactivation assays did not reveal any significant differences. For c-Myb mutational analysis of the CKII phosphorylation sites showed altered steady state DNA binding. Replacing Ser-11/12 by alanine residues resulted in increased DNA binding compared to wt c-Myb or Myb Asp-11/12 as demonstrated by up to 10-fold differences in the dissociation constants. In transactivation assays, the Ala mutant showed consistently an increased activity both on a synthetic and on the mim-1 promoter. A potential CKII phosphorylation site in c-Fos was not phosphorylated in vitro. Analysis with peptides demonstrated that a proline residue at position +1 relative to the acceptor serine was inhibitory.

Amino Acid Sequence↗
PubMed1993

Analysis of c-Myc domains involved in stimulating SV40 replication.

We have demonstrated previously that overproduction of c-Myc, N-Myc and, to a lesser extent, L-Myc facilitates the replication of simian virus 40 (SV40)-based vectors in human lymphoid cells. Using a series of c-myc deletion mutants, we investigated which c-Myc regions are important in stimulating SV40 replication. The ability of c-Myc to promote SV40 replication was significantly reduced by deletions in the second exon domain, formerly shown to be crucial for c-Myc's transforming capacity. The c-myc mutants with a disrupted basic region (b) or leucine zipper (Zip) motif were also unable to stimulate SV40 replication. These regions are implicated in protein-DNA and protein-protein interactions, respectively, suggesting that the c-Myc protein might be associated with the DNA-protein replication complex. We present data obtained from gel mobility shift assays and from an immunocomplex-binding assay substantiating this hypothesis.

Base Sequence↗
PubMed1993

Phosphorylation sites mapping in the N-terminal domain of c-myc modulate its transforming potential.

The nuclear proto-oncoprotein c-Myc is involved in the regulation of cell growth and differentiation. c-Myc is phosphorylated at multiple sites in vivo, two of which we have identified near the amino terminus. In chicken Thr-61/Ser-65 are phosphorylated, as are the comparable positions, Thr-58/Ser-62 in human c-Myc. These residues are located within a domain that is implicated in transactivation and is important for the transforming potential of the protein. Furthermore, these phosphorylation sites or nearby amino acids are frequently mutated in v-myc and in several c-myc genes from Burkitt's lymphoma cells. In vitro these two phosphorylation sites can be modified by glycogen synthase kinase 3 and mitogen activated protein kinase. To address their biological importance we mutated these amino terminal phosphorylation sites separately and together. Stably transfected Rat1A cells expressing the mutated proteins have an increased growth potential in soft agar compared to wt-c-myc transfectants. These altered transformation characteristics indicate that Myc function may be negatively regulated by the amino terminal phosphorylation.

Amino Acid Sequence↗
PubMed1993

Identification of casein kinase II phosphorylation sites in Max: effects on DNA-binding kinetics of Max homo- and Myc/Max heterodimers.

Myc proteins have been implicated in the regulation of cell growth and differentiation. The identification of Max, a basic region/helix-loop-helix/leucine zipper protein, as a partner for Myc has provided insights into Myc's molecular function as a transcription factor. Recent evidence indicates that the relative abundance of Myc and Max is important to determine the level of specific gene transcription. In this report we have identified two major in vivo phosphorylation sites in Max (Ser-2 and -11) which can be modified in vitro by casein kinase II (CKII). Phosphorylation of these sites modulates DNA-binding by increasing both the on- and off-rates of Max homo- as well as Myc/Max heterodimers. In addition, our data indicate that the steady state binding of the shorter version of Max (p21) to DNA was similar yet its rate of dissociation faster than that of longer version of Max (p22). These data argue that different Max complexes have different kinetic properties and that these can be modified by CKII phosphorylation. We propose this as an important biological mechanism by which different dimeric complexes can exchange with varying efficiencies on DNA, thereby responding to changes in cell growth conditions.

Amino Acid Sequence↗
PubMed1992

Nuclear colocalization of c-myc protein and hsp70 in cells transfected with human wild-type and mutant c-myc genes.

Using immunofluorescence and electron microscopy we have studied the localization of wild-type and mutant c-myc proteins transiently expressed in CV-1 cells. In agreement with our previous observations, wild-type c-myc protein accumulated in large amorphous globules in the nucleus. All mutant proteins tested accumulated in the nucleus as well, but gave rise to morphologically different inclusion bodies. Many small globules appeared in cells transfected with D145-262 (deletion of amino acids 145-262), while cells transfected with D371-412 or D414-433 generated structures looking like a fine network or like beads on a string. In addition, a particulate cytoplasmic staining appeared in some cells transfected with the wild-type gene and in cells transfected with mutants D145-262 or D414-433. Since the c-myc protein has been reported to stimulate expression of exogenous hsp70 protein, we also examined the intracellular distribution of hsp70 in the transfected cells. Double immunofluorescence microscopy revealed that hsp70 codistributed with the c-myc protein in distinct globules in the nucleus of many but not all myc-positive cells. However, the levels of hsp70 transcripts were not significantly raised compared to nontransfected and vector-transfected cells. Likewise, the levels of hsp70 protein did not vary significantly. These findings indicate that overexpression of c-myc stimulates translocation of preexisting hsp70 from the cytoplasm into the nucleus, rather than influencing hsp70 expression. Conceivably, this may represent one of several mechanisms whereby the cell deals with excessive amounts of c-myc protein.

Animals↗