The functions of Myc proteins

Meichle, Albrecht

doi:10.1016/0304-419x(92)90011-m

Cited by 58 publications

(62 citation statements)

References 92 publications

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“…Similar to G1 speci®c cyclins the transcription factor c-Myc plays a key role in cellular proliferation (reviewed in Meichle et al, 1992). In serum stimulated cells c-Myc is induced as an immediate early response gene.…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown that both micro-injection of cMyc into the nuclei of quiescent cells or the expression of c-Myc through conditional alleles rapidly drives the cells through G1 into the S-phase (Eilers et al, 1991) and that inhibition of Myc function often arrests cells in the G1 phase of the cell cycle. Through the work of recent years a functional role of Myc family proteins as regulators of gene expression has emerged (reviewed in Meichle et al, 1992). The Myc transcription factors contain a transactivation domain at the amino terminal end and a basic region directly followed by a helix ± loop ± helix-leucine zipper motif (b-HLHLZip) at its carboxyterminal end.…”

Section: Introductionmentioning

confidence: 99%

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Mutual requirement of CDK4 and Myc in malignant transformation: evidence for cyclin D1/CDK4 and p16INK4A as upstream regulators of Myc

Haas

Staller²,

Geisen

et al. 1997

Oncogene

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We demonstrate in this paper that CDK4 which is a G1 phase speci®c cell cycle regulator and catalytic subunit of D-type cyclins has oncogenic activity similar to Dtype cyclins themselves and is able to provoke focus formation when cotransfected with activated Ha-ras into primary rat embryo ®broblasts. Surprisingly, using two di erent mutants we show that CDK4's ability to bind to p16 INK4a and not its kinase activity is important for its transforming potential. In addition, p16 INK4a but not a mutant form that is found in human tumours can completely abrogate focus formation by CDK4 suggesting that CDK4 can malignantly transform cells by sequestering p16 INK4a or other CKIs. We demonstrate that both cyclin D1 and CDK4 functionally depend on active Myc to exert their potential as oncogenes and vice versa that the transforming ability of Myc requires functional cyclin D/CDK complexes. Moreover, we ®nd that p16 INK4a and the Rb related protein p107 which releases Myc after phosphorylation by cyclin D1/CDK4 e ciently block Myc's activity as a transcriptional transactivator and as an oncogene. We conclude that both p16 INK4a and cyclin D/CDK4 complexes are upstream regulators of Myc and directly govern Myc function in transcriptional transactivation and transformation via the pocket protein p107.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutual requirement of CDK4 and Myc in malignant transformation: evidence for cyclin D1/CDK4 and p16INK4A as upstream regulators of Myc

Haas

Staller²,

Geisen

et al. 1997

Oncogene

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“…In addition to the regulation of cyclin E or cyclin D expression through the modulation of the promotor, the enzymatic activity of D-and E-type cyclin/CDK complexes is regulated independently on a posttranscriptional level. The transcription factor Myc, for example, which is a paradigmatic immediate early factor in response to mitogen stimulation with a clear involvement in G1 progression (for a review see Meichle et al, 1992) may be responsible for cyclin E/ CDK2 activation without changing the steady state level of the cyclin E or CDK2 protein itself (Steiner et al, 1995). The cyclin dependent kinase inhibitors (CKIs) p27 and p21 both inhibit D-and E-type cyclin/CDK activity and at least D-type cyclin/CDK complexes seem to depend on the activity of Myc to exert their function in G1 progression or for their activity as oncoproteins (Roussel et al, 1995;Haas et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Malignant transformation by cyclin E and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4

Haas

Johannes²,

Geisen

et al. 1997

Oncogene

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We demonstrate in this paper that the G1 phase speci®c cell cycle regulator cyclin E is able to provoke focus formation when cotransfected with activated Ha-ras into primary rat embryo ®broblasts (REFs). Cyclin E/Ha-ras transformed cells are highly tumorigenic in synergeneic rats, are able to form colonies in soft agar and show protection towards apoptosis upon serum starvation or DNA damage compared to cells transformed by the combination of Myc, cyclin D1 or SV40 large T-antigen and Ha-ras. Lines that were established after cyclin E/ Ha-ras or cyclin D1/Ha-ras transformation contain a large percentage of polyploid cells. This was not observed in cells transformed with other oncoproteins and Ha-ras pointing to an involvement of D-and E type cyclins in genomic instability. The cyclin dependent kinase inhibitors p21 and p27 but also p16 completely abrogate focus formation by cyclin E and Ha-ras suggesting that the oncogenic activity of cyclin E still requires functional G1 speci®c cyclin/CDK complexes. Moreover, inhibition of Myc function also blocks the oncogenic activity of cyclin E indicating a requirement of Myc for cyclin E function. The ®ndings presented here demonstrate that cyclin E can act as an oncoprotein with a potential involvement in genomic instability and the prevention of cell death. Our data also present more evidence for a strict functional interdependency between G1 cyclin/CDK complexes and c-Myc.

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“…Cancer development is a complex, multistep process characterized by the abnormal activation of cellular proto-oncogenes and the loss of function of tumour suppressor genes (Vogelstein and Kinzler, 1993). A central role in the regulation of cell growth and differentiation is assigned to the c-myc proto-oncogene (Meichle et al, 1992). The c-myc gene is located to 8q24 (Taub et al, 1982) and it encodes a 439 amino acid phosphoprotein of 62 kDa with a predominantly nuclear localization (Cole, 1986).…”

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confidence: 99%

Extra c-myc oncogene copies in high risk cutaneous malignant melanoma and melanoma metastases

et al. 2001

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Summary Amplification and overexpression of the c-myc gene have been associated with neoplastic transformation in a plethora of malignant tumours. We applied interphase fluorescence in situ hybridization (FISH) with a locus-specific probe for the c-myc gene (8q24) in combination with a corresponding chromosome 8 α-satellite probe to evaluate genetic alterations in 8 primary melanomas and 33 advanced melanomas and compared it to 12 melanocytic nevi, 7 safety margins and 2 cases of normal skin. Additionally, in metaphase spreads of 7 melanoma cell lines a whole chromosome 8 paint probe was used. We investigated the functionality of the c-myc gene by detecting c-myc RNA expression with RT-PCR and c-myc protein by immunohistochemistry. 4/8 primary melanomas and 11/33 melanoma metastases showed additional c-myc signals relative to the centromere of chromosome 8 copy number. None of the nevi, safety margins or normal skin samples demonstrated this gain. In 2/7 melanoma cell lines (C32 and WM 266-4) isochromosome 8q formation with a relative gain of c-myc copies and a loss of 8p was observed. The highest c-myc gene expression compared to GAPDH was found in melanoma metastases (17.5%). Nevi (6.6%) and primary melanomas (5.0%) expressed the c-myc gene on a lower level. 72.7% of the patients with c-myc extra copies had visceral melanoma metastases (UICC IV), patients without c-myc gain in 35.0% only. The collective with additional c-myc copies also expressed the gene on a significantly higher level. These results indicate that a c-myc gain in relation to the centromere 8 copy number might be associated with advanced cutaneous melanoma.

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The functions of Myc proteins

Cited by 58 publications

References 92 publications

Mutual requirement of CDK4 and Myc in malignant transformation: evidence for cyclin D1/CDK4 and p16INK4A as upstream regulators of Myc

Mutual requirement of CDK4 and Myc in malignant transformation: evidence for cyclin D1/CDK4 and p16INK4A as upstream regulators of Myc

Malignant transformation by cyclin E and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4

Extra c-myc oncogene copies in high risk cutaneous malignant melanoma and melanoma metastases

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